Substituted 1,2,3-triazole angiotensin II antagonists

ABSTRACT

Substituted pyrroles, pyrazoles and triazoles such as   &lt;IMAGE&gt;   and &lt;IMAGE&gt;  and their pharmaceutically suitable salts are useful as antihypertensive agents and for treatment of congestive heart failure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 07/279,193, filed Dec. 6,1988, now U.S. Pat. No. 5,015,651, which is a continuation-in-part ofU.S. application Ser. No. 07/141,669, filed Jan. 7,1988, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to novel, substituted pyrrole, pyrazole andtriazole compounds, processes for their preparation, pharmaceuticalcompositions containing them, their use as antihypertensive agents, andas a treatment for congestive heart failure in mammals.

2. Background Including Prior Art

The compounds of this invention inhibit the action of the hormoneangiotensin II (AII) and are useful therefore in alleviating angiotensininduced hypertension. The enzyme renin acts on a blood plasmaα-globulin, angiotensinogen, to produce angiotensin I, which is thenconverted by angiotensin converting-enzyme to AII. The latter substanceis a powerful vasopressor agent which has been implicated as a causitiveagent for producing high blood pressure in various mammalina species,such as the rat, dog, and man. The compounds of this invention inhibitthe action of AII at its receptors on target cells and thus prevent theincrease in blood pressure produced by this hormone-receptorinteraction. By administering a compound of this invention to a speciesof mammal with hypertension due to AII, the blood pressure is reduced.The compounds of this invention are also useful for the treatment ofcongestive heart failure.

M. Gall in U.S. Pat. No. 4,577,020, issued Mar. 18, 1986, disclosesanti-psychotic triazoles of the formula: ##STR2## or an enantiomer orstereoisomer thereof, wherein R₄ is

(a) hydrogen

(b) (C₁ -C₃)alkyl,

(c) --CH₂ OH,

(d) --CH₂ OCOCH₃,

(e) --S(O)_(q) CH₃,

(f) --SCH₂ CH₃, or

(g) --R₁₅ ;

wherein R₅, R₁₅, and R₂₅ are the same or different and are

(a) phenyl substituted by zero to 2 chloro, fluoro, bromo, alkyl of fromone to 3 carbon atoms, nitro, or alkoxy of from one to 3 carbon atoms,or

(b) phenyl substituted by one trifluoromethyl and zero to one of theprevious phenyl substituents;

wherein W₁ is

(a) cis--C(R₃)═CH--CH₂ NR₁ R₂,

(b) trans--C(R₃)═CH--CH₂ NR₁ R₂,

(c) --C(CH₃)(OR₁₄)--CH₂ --CH₂ NR₁ R₂,

(d) a substituent of the Formula III, or ##STR3## (e) a substituent ofthe Formula IV; ##STR4## wherein --NR₁ R₂ is (a) --N(CH₃)--CH₂ (CH₂)_(m)--R₂₅,

(b) --NH--CH₂ (CH₂)_(m) R₂₅,

(c) a substituent of the Formula V, ##STR5## (d) a substituent of theFormula VI, ##STR6## (e) a substituent of the Formula VII, or ##STR7##(f) --N(CH₃)--(CH₂)₃ --CH(R₅₁)₂ ; wherein R₁₄ is

(a) hydrogen

(b) --COCH₃, or

(c) --COCH₂ CH₃ ;

wherein R₅₁ is

(a) phenyl,

(b) p-fluorophenyl, or

(c) p-chlorophenyl;

wherein R₃ is

(a) hydrogen or

(b) methyl;

wherein the dotted line represents a single or double bond;

wherein m is an integer of from one to 2, inclusive;

wherein n is an integer of from zero to 3, inclusive; and

wherein

q is an integer of from zero to 2, inclusive;

or a pharmacologically acceptable acid addition salt;

or solvate or hydrate thereof.

Hirsch, et al., in European Patent Application 165,777, filed June 14,1985, disclose N-substituted imidazole and triazole compounds inpreparation of medicaments for inhibiting aromatase or preventing ortreating estrogen dependent diseases. These compounds are described bythe following formula: ##STR8## wherein R is ##STR9## hydrogen, C₃ -C₈cycloalkyl, C₁ -C₄ alkyl, or acetenyl;

X is ##STR10## hydrogen, pyridyl, or 5-pyrimidyl, or R and X, when takentogether, are ═CH₂, or when taken together with the carbon atom to whichthey are attached form a cycloalkyl ring of 5-8 carbon atoms; and Q ishydrogen or methyl;

where

R₁ is hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, phenyl,methylthio, methyl, ethyl, nitro, trifluoromethyl, or ##STR11## R₂, R₄,R₅, R₆, R₇ and R₈ are independently hydrogen, chloro, or fluoro;

or R₁ and R₂, when taken together with the benzene ring to which theyare attached, form a naphthalene ring;

R₃ is hydrogen, fluoro, chloro, trifluoromethyl, methoxy, or nitro;

n is 1 or 2, and

E and G are independently N or CH, provided that E and G may not be N atthe same time.

Japanese Patent Application J4 9101-372 discloses anti-inflammatorypyrazoles of the formula ##STR12## where R is tolyl, p-nitrophenyl,benzyl and phenethyl.

Japanese Patent Application J4 9042-668 discloses the preparation of1-p-chlorobenzyl-3-methyl-2-pyrazolin-5-one. ##STR13##

Pals et al., Circulation Research, 29, 673 (1971) describe that theintroduction of a sarcosine residue in position 1 and alanine inposition 8 of the endogenous vasoconstrictor hormone AII to yield an(octa)peptide that blocks the effects of AII on the blood pressure ofpithed rats. This analog, [Sar¹, Ala⁸ ] AII, initially called "P-113"and subsequently "Saralasin", was found to be one of the most potentcompetitive antagonists of the actions of AII, although, like most ofthe so-called peptide-AII-antagonists, it also possessed agonisticactions of its own. Saralasin has been demonstrated to lower arterialpressure in mammals and man when the (elevated) pressure is dependent oncirculating AII (Pals et al., Circulation Research, 29, 673 (1971);Streeten and Anderson, Handbook of Hypertension, Vol. 5, ClinicalPharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), ElsevierScience Publishers B.V., p. 246 (1984). However, due to its agonisticcharacter, saralasin generally elicits pressor effects when the pressureis not sustained by AII. Being a peptide, the pharmacological effects tosaralasin are relatively short-lasting and are only manifest afterparenteral administration, oral doses being ineffective. Although thetherapeutic uses of peptide AII-blockers, like saralasin, are severelylimited due to their oral ineffectiveness and short duration of action,their major utility is as a pharmaceutical standard.

To date there are no known non-peptide antagonists of AII which areuseful orally or which bind in vitro in the IC₅₀ ranges we observe,other than those disclosed in the co-pending U.S. applicationsidentified above.

SUMMARY OF THE INVENTION

This invention includes novel, substituted pyrroles, pyrazoles andtriazoles, processes for their preparation, pharmaceutical compositionscontaining them, and their use as antihypertensive agents, and as atreatment for congestive heart failure in mammals. The heterocycliccompounds of the invention have the structural formula (I) ##STR14## orpharmaceutically suitable salts thereof, wherein

X, Y and Z are independently N or CR² with the proviso that

1) when R² ≠H, then only one of X, Y or Z can be CR² ;

2) when Z=N then Y and X≠CR² ; or

3) when Y=N then Z and X≠CR² ; and

4) when X=Y=N, then Z≠N;

5) when X=N, Y=Z=CR², then with respect to Y, R² ≠C₃₋₄ alkyl or C₄alkenyl and with respect to Z, R² ≠H or Cl and R¹ ≠(CH₂)_(n) OR⁴ wheren=1 and R⁴ =C₁ alkyl, A≠carbon carbon single bond, R³ ≠CO₂ H and R⁵ ≠H.

A is a carbon carbon single bond, CO, O, NHCO, OCH₂ ;

R¹ is alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbonatoms or (CH₂)_(n) OR⁴ provided that when R¹ is (CH₂)_(n) OR⁴ then R² isH, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbonatoms;

R² is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6carbon atoms; ##STR15## R³ is --CO₂ H, --NHSO₂ CF₃ ; or ##STR16## R⁴ isH or alkyl of 1-4 carbon atoms; R⁵ is H, halogen, NO₂, methoxy, or alkylof 1 to 4 carbon atoms;

R⁶ is H, alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbonatoms, (CH₂)_(m) C₆ H₅, OR⁷ or NR⁸ R⁹ ;

R⁷ is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbonatoms, phenyl or benzyl;

R⁸ and R⁹ independently are H, alkyl of 1 to 4 carbon atoms, phenyl,benzyl or NR⁸ R⁹ taken together form a ring of the formula ##STR17## Qis NR¹⁰, O or CH₂ ; R¹⁰ is H, alkyl of 1 to 4 carbon atoms or phenyl;

R¹¹ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbonatoms, (CH₂)_(p) C₆ H₅ ;

R¹² is H, alkyl of 1 to 4 carbon atoms; or acyl of 1 to 4 carbon atoms;

m is 0 to 6;

n is 1 to 6;

p is 0 to 3;

r is 0 to 1;

t is 0 to 2.

Preferred are compounds of Formula (I)

wherein:

A is a carbon-carbon single bond, or NHCO;

R¹ is alkyl, alkenyl or alkynyl each of 3 to 5 carbon atoms;

R² is H, alkyl, alkenyl or alkynyl each of 3 to 5 carbon atoms;##STR18## or (CH₂)_(n) F; R³ is --CO₂ H, --NHSO₂ CF₃ and ##STR19## R⁴ isH or CH₃ R⁵ is H;

R⁶ is H, alkyl of 1 to 6 carbon atoms, OR⁷, or NR⁸ R⁹ ;

R⁷ is alkyl of 1 to 6 carbon atoms;

R⁸ and R⁹ independently are H, alkyl of 1 to 4 carbon atoms, or takentogether with the nitrogen form the ring ##STR20## R¹¹ is CF₃, alkyl of1 to 4 carbon atoms or phenyl; m is 0 to 3;

n is 1 to 3;

and pharmaceutically suitable salts thereof.

More preferred are compounds of Formula (I)

wherein

A is a carbon-carbon single bond

R¹ is alkyl or alkenyl of 3 to 5 carbon atoms or CH₂ OR⁴ ; provided thatwhen R¹ is CH₂ OR⁴ then R² is alkyl or alkenyl of 3 to 5 carbon atoms;

R² is alkyl or alkenyl of 3 to 5 carbon atoms, CH₂ OR⁴, COR⁶, ##STR21##R⁶ is H, OH, alkyl of 1 to 4 carbon atoms; R⁷ is alkyl of 1 to 4 carbonatoms;

and pharmaceutically acceptable salts.

Specifically preferred compounds because of their antihypertensiveactivity are:

3-Methoxymethyl-5-n-propyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,4-triazole;

3-Methoxymethyl-5-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole;

5-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,3-triazole;

5-Methoxymethyl-3-n-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole;

3-carboxy-5-n-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

5-n-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrrole-2-carboxylic acid

and pharmaceutically suitable salts thereof.

Pharmaceutically suitable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences, 17th Edition, page 1418 (1985). It is wellknown to one skilled in the art that an appropriate salt form is chosenbased on physical and chemical stability, flowability, hygroscopicityand solubility. Preferred salts of this invention for the reasons citedabove include potassium, sodium, calcium and ammonium salts.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of Formula (I) may be prepared using the reactionsand techniques described in this section. The reactions are performed ina solvent appropriate to the reagents and materials employed andsuitable for the transoformation being effected. It is understood bythose skilled in the art of organic synthesis that the functionalitypresent on the heterocycle and other portions of the molecule must beconsistent with the chemical transformations proposed. This willfrequently necessitate judgement as to the order of synthetic steps,protecting groups required, deprotection conditions, and activation of abenzylic position to enable attachment to nitrogen on the heterocyclicnucleus. Throughout the following section, not all compounds of Formula(I) falling into a given class may necessarily be prepared by allmethods described for that class. Substituents on the starting materialsmay be incompatible with some of the reaction conditions required insome of the methods described. Such restrictions to the substituentswhich are compatible with the reaction conditions will be readilyapparent to one skilled in the art and alternative methods describedmust then be used.

The approaches described for each class of heterocycles generallyencompass two major strategies. The first involves N-alkylation of apreformed mono- or disubstituted heterocycle with an appropriatelyfunctionalized benzyl halide. The second involves cycloaddition orcyclocondensation of two or three strategically prepared components togenerate directly the heterocycle possessing the functionality needed toproduce the final products, following relatively minor transformations(e.g., amide or ether bond formation, deprotection). The approach usedfor a given example will depend on the availability of startingmaterials and compatibility of pendant functionality to the requiredreaction conditions.

In cases where more than one regioisomer was produced during synthesis(e.g., 1,2,3-triazoles, pyrazoles), unequivocal identification of eachregioisomer was gained through Nuclear Overhauser Effect (NOE) NMRspectra.

Most of the major reaction pathways leading to 1,2,3-triazoles involveazides and several reviews have been published in this area, G. L'abbe',Chem. Rev. 69, 345 (1969); T. Srodsky, in "The Chemistry of the AzidoGroup", Wiley, N.Y. (1971), p. 331. The most common and versatileapproach is the thermal cycloaddition of azides to alkynes; H. Wamhoffin "Comprehensive Heterocyclic Chemistry", S. R. Katritzky (Ed.),Pergamon Press, New York (1984), Vol. 5, p. 705; K. T. Finley, Chem.Heterocycl. Compd. 39, 1 (1980). A wide range of functionality on bothalkyne and azide components are tolerated in the thermal cycloadditionreaction and the approach to a specific target is generally determinedby the availability of requisite precursors. Thus, disubstituted1,2,3-triazoles, such as 4 in Scheme 1, may be prepared by heating aterminal alkyne 1 with an azide such as 3. Although the 1,4-isomer isoften produced regiospecifically, a mixture of 1,4- and 1,5-regioisomersmay result. Alternatively, a 4(5)-substituted-1,2,3-triazole may beN-alkylated with an appropriately functionalized benzyl halide such as5. In this approach, any or all of the three ring nitrogens may competein the alkylation depending upon the nature of the substituents oneither component and the specific reaction condition, H. Gold, LiebigsAnn. Chem., 688, 205 (1965); T. L. Gilchrist, et al., J. Chem, Soc.,Perkin Trans. 1, 1 (1975). Thus, compound 6 may also be produced.

As shown in Scheme 2, compounds of the formulas 15 where A=NHCO may beprepared from aniline precursor 11 which is available by reduction ofthe corresponding nitrobenzyl derivative 9. This key intermediate (9)can be made by cyloaddition or alkylation chemistry as describedpreviously for Scheme 1. Compounds of the formula 15 where R³ =CO₂ H maybe prepared by reacting anilines 11 with a phthalic anhydride derivativein an appropriate solvent such as benzene, chloroform, ethyl acetate,etc. Often the phthalamic acids 14 precipitate from solutions with thereactants remaining behind as described by M. L. Sherrill, et al., J.Amer. Chem. Soc., 50, 474 (1928). Also, compounds of the formula 15where R³ =NHSO₂ CF₃ or tetrazoyl can be prepared by reacting therequisite acid chlorides 13 with anilines 11 by either aSchotten-Baumann procedure or simply stirring the reactants in a solventsuch as methylene chloride in the presence of a base such as sodiumbicarbonate, pyridine, or triethylamine. Likewise, anilines 11 may becoupled with an appropriate carboxylic acid via a variety of amidebond-forming reactions such as dicyclohexyl carbodiimide coupling, azidecoupling, mixed anhydride synthesis, or other coupling proceduresfamiliar to one skilled in the art.

Scheme 3 illustrates the approach when A=OCH₂ in compounds of theformula 22. Hydrolysis of the methyl ether (18) or benzyl ether (19)affords hydroxy compounds (20) which can be alkylated with theappropriate benzyl halides (21) to give 22. In the case of the methylethers (18), the hydrolysis can be effected by heating the ether attemperatures of 50°-150° C. for 1-10 hours in 20-60% hydrobromic acid,or heating at 50°-90° C. in acetonitrile with 1-5 equivalents oftrimethylsilyl iodide for 10-50 hours followed by treatment with water.Hydrolysis can also be carried out by treatment with 1-2 equivalents ofboron tribromide in methylene chloride at 10°-30° C. for 1-10 hoursfollowed by treatment with water, or by treatment with a Lewis acid suchas aluminum chloride and 3-10 equivalents of thiophenol, ethanedithiolor dimethyl disulfide in methylene chloride at 0°-30° C. for 1-20 hoursfollowed by treatment with water, or by treatment with aluminum chlorideand 3-10 equivalents of thiophenol, ethanedithiol or dimethyl disulfidein methylene chloride at 0°-30° C. for 1-20 hours followed by treatmentwith water. Hydrolysis of benzyl ethers (19) can be accomplished byrefluxing in trifluoroacetic acid for 0.2-1 hours or by catalytichydrogenolysis in the presence of a suitable catalyst such as 10%palladium on carbon and 1 atm of hydrogen. Deprotonation of (20) with abase, such as sodium methoxide or sodium hydride in a solvent such asdimethylformamide (DMF) or dimethylsulfoxide (DMSO) at room temperaturefollowed by alkylation with an appropriate benzyl halide at 25° C. for2-20 hours affords compounds of the formula (22).

As shown by Scheme 4, the functionalized benzyl azides (25) may beprepared from the corresponding benzyl halides (24) via displacementwith an azide salt such as sodium azide in a polar solvent such asdimethylformamide, dimethylsulfoxide or under phase transfer conditionsat room temperature for 18-48 hours. The benzyl bromides (24) may bemade by a variety of benzylic halogenation methods familiar to oneskilled in the art; for example, benzylic bromination of toluenederivatives (23) occurs in an inert solvent such as carbon tetrachloridein the presence of a radical initiator such as benzoyl peroxide attemperatures up to reflux conditions.

Scheme 5 illustrates the preferred approaches for incorporation of A asa single bond (31), ether (34), and carbonyl (37) linker. The biphenyls(31) are prepared by Ullman coupling of 29 and 30 as described in"Organic Reactions",2, 6 (1944). Ethers (34) can be prepared analogouslyby an Ullman ether condensation between phenols (32) and halides (33) asdescribed in Russian Chemical Reviews, 43, 679 (1974). The benzophenoneintermediates (37) are generally available through classicalFriedel-Crafts acylation between toluene (35) and the appropriatebenzoyl halides (36), G. Olah, "Friedel-Crafts and Related Reactions",Interscience, New York (1963-1964).

Alternatively, the substituted biphenyl precursor (40) and correspondingesters (41) can be prepared by reaction of methoxy oxazoline (39) withtolyl Grignard reagents, S. I. Meyers and E. D. Mikelich, J. Am. Chem.Soc., 97, 7383 (1975) as shown in Scheme 6.

The substituted biphenyl tetrazoles (31; where R³ =CN₄ H) can beprepared from the nitrile precursors (R³ =CN) by a variety of methodsusing hydrazoic acid (Scheme 7, equation b). For example, the nitrile(31) can be heated with sodium azide and ammonium chloride indimethylformamide at temperatures between 30° C. and reflux for 1-10days, J. P. Hurwitz and A. J. Thomson, J. Org. Chem., 26, 3392 (1961).Preferably, the tetrazole is prepared by the 1,3-dipolar cycloadditionsof trialkyltin or triaryltin azides to the appropriately substitutednitrile (31) as shown in Scheme 7, equation a); described by S. Kozuma,et al., J. Organometallic Chem., 337 (1971). The required trialkyl ortriaryltin azides are made from the corresponding trialkyl or triaryltinchlorides and sodium azide. The pendant tin group of 42 is removed byacidic or basic hydrolysis and the resultant free tetrazole may beprotected with the trityl group by reaction with trityl chloride andtrimethylamine to provide 43. Bromination as previously describedaffords 24. Other protecting groups such as p-nitrobenzyl and1-ethoxyethyl may be used instead of the trityl group to protect thetetrazole moiety as needed. Such protecting groups, among others, can beintroduced and removed by procedures found in T. W. Greene, ProtectiveGroups in Organic Chemistry, Wiley-Interscience (1980). ##STR22##

The more common and unambiguous syntheses of 1,2,4-triazoles fromacyclic precursors generally involve hydrazine derivatives, due to theease of forming C--N and C═N bonds over the relative difficulty offorming N--N bonds, J. B. Palya in Comprehensive Heterocyclic Chemistry,A. R. Katritzky (Ed.), Pergamon Press, New York (1984), Vol. 5, p. 762.Synthesis of compounds with substituents on N-4 may be approached bymethods illustrated in Scheme 8. Reaction of an intimate mixture oforthoesters (45), acylhydrazines (46), and amines (47) in an appropriatesolvent like xylenes or any of the lower alcohols at or near the refluxtemperature for 1-24 hours produces 1,2,4-triazoles (48), P. J. Nelsonand K. T. Potts, J. Org. Chem. 27, 3243 (1962); Y. Kurasawa et al., J.Heterocyclic Chem., 23, 633 (1986). Alternative access to suchstructures may also be gained by condensing N,N'-diacylhydrazines (49)with amines (47) or cyclocondensation of appropriately substitutedamidrazones such as ( 50), Comp. Het. Chem., Vol. 5, p. 763.

the versatility of this approach is expanded upon in Scheme 9. Groups R¹and R² may be carried by either the orthoester (45, 52) or acylhydrazine(46, 51) moieties depending upon their availability. Experimentally, theorthoester and acylhydrazine are first reacted to produce, presumably,1,2,4-oxadiazoles (53) which may be isolated (if stable) but arecommonly reacted in situ with amines (47) (or 58 or 64; Schemes 10 and11) to ultimately afford (48). Alternatively, oxadiazoles (53) may betransformed to simpler triazoles (54) by treatment with ammonia.Alkylation of this species gives rise to a mixture of N-1 and N-2substituted products (55), K. T. Potts, Chem. Rev., 61, 87 (1961); K.Schofield, M. R. Grimmett and B. R. T. Keene; Heteroaromatic NitrogenCompounds: The Azoles, Cambridge University Press, Cambridge, (1976), p.81. N-4 alkylation of simple 1,2,4-triazoles has been observed onlyrarely, M. R. Atkinson and J. B. Palya, J. Chem. Soc. 141 (1954). Analternative approach to such N-1 and N-2 substituted triazoles may beillustrated by reactions between (56) and benzylhydrazines (57). In(56), the dotted lines leave the presence or absence of a bond open,thus allowing possible reactants like (R¹ COX, R² COX and NH₃) or (R¹CONH₂ and R² COX) or (R¹ COX and R² CONH₂) or (R¹ CONHCOR²); X standsfor a suitable leaving group like Cl, OH, or H₂ O.

For compounds in which A=NHCO, the approach utilizes the commerciallyavailable 4-nitrobenzylamine (58) in place of the more highlyfunctionalized benzylamines (47). This affords N-4-substitutednitrobenzyltriazoles (59) which may be further elaborated toamide-linked systems (62) and (63) in a manner analogous to thatdescribed previously (Scheme 2). Alternative access to (59) may beattained through N,N'-diacylhydrazines (49) or amidrazones (60) in amanner described earlier in Scheme 8. The related N-(2) substitutedsystems may be approached by alkylation of (54) with 4-nitrobenzylbromide (24) as generalized in Scheme 9.

Likewise, for compounds in which A=OCH₂, Scheme 11 shows how use ofcommercially available 4-methoxy- or 4-benzyloxybenzylamines (64) mayproduce (65) which can be deprotected and further functionalized asdescribed previously (Scheme 3).

Orthoesters such as (45) and (52) (Scheme 12) are most generallyavailable through alcoholysis of imidate ester hydrochlorides (70) whichare usually prepared from the corresponding nitriles (69) by addition ofalcohols (usually methanol or ethanol) in the presence of anhydroushydrogen chloride, R. H. De Wolfe, Carboxylic Ortho Acid Derivatives:Preparation and Synthetic Applications, Academic Press, New York, pp.1-54. The synthesis is usually conducted as a two-step process, thefirst being preparation and isolation of the imidic ester hydrochloride(70). The lower aliphatic members of this class are often prepared byaddition of a slight excess of anhydrous hydrogen chloride to a chilledsolution of the nitrile in a slight excess of an alcohol. A suitablyinert solvent like ether, benzene, chloroform, nitrobenzene or1,4-dioxane is then added, the resulting mixture is allowed to stand inthe cold (60° C.) for several hours to a week and the product iscollected by suction filtration and washed free of residual solvent andhydrogen chloride, S. M. McElvain and J. W. Nelson, J. Amer. Chem. Soc.,64, 1825 (1942); S. W. McElvain and J. P. Schroeder, J. Amer. Chem.Soc., 71, 40 (1949). These imidate esters hydrochlorides are convertedto orthoesters by stirring with an excess of an alcohol (generally thesame one used above) for up to 6 weeks or, more efficiently, byrefluxing the imidate ester hydrochloride with a five to tenfold excessof the alcohol in ether for up to 2 days. Even higher yields can beobtained by stirring the imidate ester at room temperature in a mixtureof the alcohol and petroleum ether, S. M. McElvain and C. L. Aldridge,J. Am. Chem. Soc., 75, 3987 (1953); Ibid, 80, 3915 (1958). Orthoestersprepared by the above described method may incorporate a rather largearray of functionality, including aliphatic, alkenyl, alkynyl, aromatic,halogen, ether, ester, amino, nitro, thio (in various oxidation states),amide, or urethane groups. Another approach, less commonly used,involves electrolysis of trihalomethyl compounds (71) or α-halo ethers,though this approach is limited to halides having no α-hydrogens and isgenerally applicable to the synthesis of trialkyl orthobenzoates, H.Kevart and M. B. Price, J. Amer. Chem. Soc., 82, 5123 (1960); R. A.McDonald and R. S. Krueger, J. Org. Chem., 31, 488 (1966).

Acyl hydrazines (46, 51) may be prepared in a straightforward manner byreaction of the corresponding esters (72; X=OR) with hydrazine (orhydrazine monohydrate) in an appropriate solvent like alcohol,acetonitrile, DMF or pyrroline at temperatures of 0° C. to reflux for 1to 18 hours (Scheme 13). The related acid (X=OH), anhydride (X=OCOR),amide (X=NH₂) or acid halide (X=Cl, Br) may also be used, but the morereactive acid derivatives (e.g., acid halides) are generally used forpreparation of N,N'-diacylhydrazines (49), except in those instanceswhere the larger size R¹ (2) groups lead to relatively less reactivespecies.

Symmetrical N,N'-diacylhydrazines (49) are best prepared by reactions of2 equivalents of an acylhalide (72; X=Cl, Br) with hydrazine or,alternatively, by oxidation of the corresponding monoacylhydrazine."Mixed" N,N'-diacylhydrazines (49) are obtained through a two-stepprocess by first preparing the monoacylhydrazine (46, 51) followed byits reaction with the appropriate acyl halide (72; X-Cl, Br).

Benzylhydrazines (57; 77) may be prepared by a variation of the Raschigprocess for hydrazine by substituting benzyl amines (76) for ammonia andaminating these with chloramine or hydroxylamine-O-sulfonic acid, W. W.Schienl, Aldrichimica Acta, 13, 33 (1980) as illustrated in Scheme 14,equation b). Alkylhydrazines have also been prepared from alkyl halidesor sulfates. Although the tendency here is towards polyalkylation,monoalkylation is favored by bulky groups (i.e., benzyl, 24) or by useof a large excess of hydrazine, S. N. Kast, et al., Zh. Obshch, Khim,33, 867 (1963); C. A., 59, 8724e (1963).

Benzylamines (76) may be prepared by a variety of methods, some of themore common ones being illustrated in Scheme 14, equation a). The mostdirect approach, aminolysis of halides, is often accompanied by theformation of secondary, tertiary and even quaternary amines, J. Amer.Chem. Soc. 54, 1499, 3441 (1932).

A more efficient approach involves reduction of the correspondingbenzylazides (25) by catalytic reduction, hydride reagents,triphenylphosphine or stannous chloride, among others, S. N. Maiti, etal., Tetrahedron Letters, 1423 (1986 ). Reaction of benzylhalides (24)with potassium (or sodium) phthalimide followed by hydrolysis orhydrazinolysis of the intermediate N-benzylphthalimides (73) constitutesthe Gabriel Synthesis of primary amines and is highly attractive fromthe standpoint of the wide range of functional groups tolerated andmildness of conditions for both steps, M. S. Gibson and R. W. Bradshaw,Angew. Chem. Int. Ed. Engl. 7, 919 (1968). Reductive amination ofbenzaldehydes (75) with ammonia and hydrogen using a nickel catalyst isanother common approach, Organic Reactions 4, 174 (1948). Reduction ofbenzonitriles (74) by metal hydrides or catalytic hydrogenation is alsocommonly employed, J. Chem. Soc. 426 (1942); J. Amer. Chem. Soc., 82,681, 2386 (1960); Organic Reactions, 6, 469 (1951). Other reagents havebeen employed for conversion of intermediates (24), (74) and (75) to(76), J. T. Harrison and S. Harrison, Compendium of Organic SyntheticMethods, John Wiley and Sons, New York, Vol. 1-5 (1971-1984). ##STR23##

A general and versatile approach to pyrazoles involves condensation of a1,3-difunctional compound (usually dicarbonyl) with hydrazine or itsderivatives, as shown in Scheme 15 for pyrazoles of the formula 80, andreviewed by G. Corspeau and J. Elguerv, Bull. Soc. Chim. Fr. 2717(1970). Rarely have pyrazoles been prepared in which the N-N bond is thelast step of the ring closure, J. Elguerv in Comprehensive HeterocyclicChemistry, S. R. Katritzky (Ed.) Pergamon Press, New York, Vol. 5(1984), p. 274; J. Barluenga, J. Chem. Soc., Perkin Trans. 1, 2275(1983).

For examples, where A=NHCO or OCH₂, the compounds of formula 84 and 87may be constructed via the nitrobenzyl (81) and alkoxybenzyl (85)intermediates, as illustrated in Schemes 16 and 17, respectively, asdescribed for the triazole series (Schemes 2 and 3).

The condensation of 1,3-dicarbonyl compounds with hydrazine hydrate orbenzyl hydrazine derivatives is generally carried out by admixture ofthe two components in a suitable solvent like a lower alcohol, ether, orTHF at 0° C. to the reflux temperature for 1-18 hours.

Alkylative of pyrazoles (79) can be carried out either by reactions of apreformed sodium (or potassium) pyrazole salt with an appropriatelysubstituted benzyl halide (5) in a polar solvent like DMF or DMSO at 0°C. to room temperature or by reaction between free pyrazoles (79) and(5) in a like solvent and an acid scavenger such as sodium bicarbonateor potassium carbonate, as described for the triazole series.

In either approach, mixtures of N-1 and N-2 substituted pyrazoles (80,81, or 85) of varying ratios are generally obtained which can beseparated by conventional chromatographic methods.

The synthesis of 1,3-dicarbonyl compounds has received considerableattention in the literature and most of the major approaches towards1,3-diketones (78) of interest in this invention are illustrated byScheme 18.

Esters (72; X=OR) can be reacted with methyl ketones (88) using baseslike sodium ethoxide, sodium hydride or sodium amide in a suitablesolvent like alcohol, DMF, DMSO or benzene at 0° C. to reflux for 4-18hours with 30-70% efficiency, J. M. Sprague, L. J. Beckham and H.Adkins, J. Amer. Chem. Soc., 56, 2665 (1934). Metallation of hydrazines(89) with n-Buli followed by reaction with carboxylic acid chlorides(72; X=Cl) and subsequent hydrolysis affords 78, D. Enders and P.Wenster, Tetrahedron Lett., 2853 (1978). Metallation of 88 with thenon-nucleophilic mesityl lithium followed by acylation also affords 78,A. K. Beck, M. S. Hoelstein and D. Seeback, Tetrahedron Lett., 1187(1977); D. Seebach, Tetrahedron Lett. 4839 (1976).

As shown in Scheme 18, equation b), the addition of Grignard reagents toβ-keto carboxylic acid chlorides may be limited to monoaddition at lowtemperatures to provide 78, C. D. Hurd and G. D. Kelso, J. Amer. Chem.Soc. 62, 1548 (1940); F. Sato, M. Trone, K. Oyuro, and M. Sato,Tetrahedron Lett., 4303 (1979). Lithium dialkyl copper reagents (R₂CuLi) have also been used, Luong-Thi and Riviero, J. Organomet. Chem.77, C52 (1974). Analogously, addition of alkyllithium reagents (R² Li)to the monoanions of β-keto esters (91) also give rise to 1,3-diketones,S. N. Huckin and L. Weiler, Can. J. Chem. 52, 1379 (1974).

Eschenmoser has demonstrated a synthesis of β-diketones through a sulfurextrusion reaction of keto thioesters (92) with tributylphosphine,triethylamine and lithium perchlorate, S. Eshenmoser, Helv. Chim. Acta.,54, 710 (1971).

The rearrangement of α,β-epoxy ketones (93) to β-diketones (78)catalyzed by Pd° has been reported, R. Noyori, J. Amer. Chem. Soc. 102,2095 (1980).

Mixed anhydrides such as 95, available from carboxylic acids (94) andtrifluoracetic anhydride, have been shown to acylate alkynes (1) toproduce the enol trifluoroacetate of a β-diketone (97).Transesterification by refluxing with methanol liberates the β-diketone(78), A. L. Henne and J. M. Tedder, J. Chem. Soc. 3628 (1953). ##STR24##

Synthetic approaches towards pyrroles have received wider attention inthe literature than most any other heterocycle and numerous methods fortheir construction have been published. R. J. Sundberg in "ComprehensiveHeterocyclic Chemistry", A. R. Katritzky (Ed.), Pergamon Press, New York(1984), Vol. 4, p. 705; Synthesis, 1946, 281. The following discussionis restricted to the most common and reliable methods towards thesynthesis of pyrroles within the general scope of the invention.

The cyclizative condensation of 1,4-dicarbonyl compounds with ammonia,primary amines or related compounds, the Paal-Knorr reaction, is one ofthe most general and widely applicable pyrrole syntheses, R. A. Jonesand G. P. Bean, "The Chemistry of Pyrroles", Academic Press, London,1977; p. 77-81. The generality of this approach is primarily determinedby the availability of the dicarbonyl precursors, 98, as illustrated byScheme 19. By heating such diketones with ammonia or amines in a solventlike benzene, toluene or methylene chloride with a catalyst such assulfuric acid, acetic acid, p-toluenesulfonic acid, alumina or eventitanium tetrachloride, pyrroles like 99 may be prepared. By choosingthe appropriate arylmethylamine (76, Scheme 14) one may ultimatelyincorporate the various A-linkers into the fully elaborated pyrroles(100) using methods described earlier (Schemes 1-3). Alternatively, onemay alkylate the disubstituted pyrroles (99a) with benzyl halides (24)under conditions previously described (Schemes 1, 9 or 15) to give thesame 100.

The cyclization of diynes (101) with amines in the presence of cuprouschloride has been reported (Scheme 20, equation a), but this approach isgenerally restricted to the preparation of symmetrically substitutedpyrroles since the diynes are usually made by oxidative coupling ofalkynes, K. E. Schulte, J. Reish, and H. Walker, Chem. Ber. 98 (1965);A. J. Chalk, Tetrahedron Lett. 3487 (1972).

Furans (103) have been converted directly to pyrroles by treatment withamines but the harsh conditions required (400° C./Al₂ O₃) precludes itsgenerality. 2,5-Dialkoxytetrahydrofurans (105) have been more commonlyemployed as furan (or 1,4-dicarbonyl) equivalents and react readily withaliphatic or aromatic amines (and even weakly nucleophilic sulfonamides)to give pyrroles as shown in Scheme 20, equation b), J. W. F. Wasley andK. Chan, Synth. Commun. 3, 303 (1973). Although commercially available2,5-dialkoxytetrahydrofurans (105) (R¹ =R² =H) generally restrict one topreparing 1-substituted pyrroles, more highly substituted systems may beobtained by a three-step alcoholysis of the appropriate furans (103) tothe more highly substituted 2,5-dialkoxytetrahydrofurans (105) as shownby Scheme 20, equation b), N. L. Weinberg and H. R. Weinberg, Chem.Rev., 68, 449 (1968); N. Elming, Adv. Org. Chem., 2, 67 (1960).

The Hantzsch synthesis utilizes the condensation of α-haloketones (106)and β-ketoesters (107) in the presence of ammonia or a primary amine togive pyrroles such as (108), as shown in Scheme 21, equation a); A.Hantzsch, Chem. Ber., 23, 1474 (1890); D. C. von Beelen, J. Walters, andS. von der Gen, Rec. Trav. Chim. 98, 437 (1979). Among the numerousmodifications reported over the years, the substitution of (106) withthe readily available α-hydroxyaldehydes or nitroalkenes has expandedthe versatility and generality of this important method, D. M. McKinnon,Can. J. Chem. 43, 2628 (1965); H. George and H. J. Roth, Arch. Pharm.307, 699 (1974); C. A. Grok and K. Camenisch, Helv. Chem. Acta, 36, 49(1953).

The closely related Knorr condensation involves the reaction betweenamino carbonyl compounds (or their precursors) and carbonyl (ordicarbonyl) compounds, J. M. Patterson, Synthesis, 282 (1976).Representative methods for preparing 2,3- or 2,5-disubstituted pyrroles(111 and 114) are shown by Scheme 21, equations b) and c), S. Umio etal., Jap. Pat. 7018653, Fujisawa Pharmaceutical Co., Ltd., 1970 (C.A.73, 77039, 1970); K. Tanaka, K. Kariyone, S. Umio, Chem. Pharm. Bull.(Tokyo), 17, 611 (1969).

The elaboration of an appropriately functionalized pyrrole is anothermethod for preparing pyrroles of general formula I. Methyl (or ethyl)5-formyl-1H-pyrrole-2-carboxylate (119) is a particularly usefulintermediate as regards pyrroles claimed in this invention and has beenprepared by a number of methods as shown by Scheme 22, eq. a, W. A.Davies, A. R. Pinder and I. G. Morris, Tetrahedron 18, 405 (1962); Org.Syn. Vol. 36, p. 74; Org. Syn. Vol. 51.

More recently, Ullrich has extended the Vilsmeyer-Haack formylation ofpyrroles to include vinylogous systems such as (122) by using3-(N,N-dimethylamino)acrolein (121) as a vinylogousN,N-dimethylformamide derivative, as shown by Scheme 22, eq. b, F. W.Ullrich and E. Breitmaier, Synthesis, 641 (1983); W. Heinz, et al.,Tetrahedron, 42, 3753 (1986).

An especially attractive approach to pyrroles claimed in this inventionhas recently been reported, whereby lithiation of the6-dimethylamino-1-azafulvene dimer (125) followed by treatment with anappropriate electrophile and subsequent hydrolysis leads to5-substituted pyrrole-2-carboxaldehydes (99a; R2=CHO), as illustrated inScheme 23, J. M. Muchowski and P. Hess, Tetrahedron Lett., 29, 777(1988).

Scheme 23a illustrates generally how N-alkylation of (99a) with theappropriate benzyl halides (as discussed earlier, Schemes 1, 9 or 15),followed by standard manipulation of the pendant groups using methodsfamiliar to one skilled in the art can produce pyrroles of generalformula I (100). ##STR25##

Described herein are general methods for the preparation of specificfunctional groups on R¹ and R² claimed in this invention. As before, itis understood by those skilled in the art of organic synthesis that allfunctionality present must be consistent with the chemicaltransformations proposed.

As shown in Scheme 24, equation a), benzylic heterocycles (125) where R¹or R² =CH₂ OH may be converted to the corresponding halide, mesylate ortosylate by a variety of methods familiar to one skilled in the art.Preferably, the alcohol (125) is converted to the chloride (126) usingthionyl chloride in an inert solvent at temperatures of 20° C. to thereflux temperature of the solvent.

Chloride (126) may be displaced by a variety of nucleophiles. Forexample, excess sodium cyanide in DMSO at temperatures of 20° to 100° C.may be used to form cyanomethyl derivatives (127). These nitriles (127)may be hydrolyzed to carboxylic acids (128) by treatment with strongacid or alkali. Preferably, treatment with a 1:1 (v/v) mixture ofconcentrated aqueous hydrochloric acid/glacial acetic acid at refluxtemperatures for 2-96 hours or by treatment with 1N sodium hydroxide inan alcohol solvent such as ethanol or ethylene glycol for 2-96 hours attemperatures from 20° C. to reflux can be used. Alternatively, thenitrile group can be hydrolyzed in two steps by first stirring insulfuric acid to form the amide followed by acidic or basic hydrolysisto furnish the carboxylic acids (128).

These carboxylic acids (128) may be esterified to esters (129) usingstandard methods, for example, stirring the carboxylic acids (128) withan alcohol in a suitably inert solvent containing hydrogen chloride orsimilar catalysts, or by first converting the carboxylic acids (128) tothe corresponding acid chloride with thionyl chloride or oxalyl chloridefollowed by treatment with the appropriate alcohol. Carboxylic acids(128) may also be reduced to the corresponding hydroxymethyl compounds(130) using reductants like LiAlH₄ or B₂ H₆, thus constituting anoverall homologation for the process (125)→(130).

Alcohol derivatives (125 or 130) may be acylated to give esters (131) bya variety of procedures. As shown in Scheme 24, equation b), acylationcan be achieved with 1-3 equivalents of an acyl halide or anhydride in asuitable solvent like diethyl ether or tetrahydrofuran in the presenceof a base such as pyridine or triethylamine. Alternatively, suchalcohols (125, 130) may be acylated by reaction with a carboxylic acidand dicyclohexylcarbodiimide (DCC) in the presence of a catalytic amountof 4-(N,N-dimethylamino)pyridine (DMAP) via the procedure described byA. Hasmer, Tetrahedron Lett. 46, 4475 (1978). Treatment of 125 or 130with a solution of carboxylic acid anhydride in pyridine optionally witha catalytic amount of DMAP at temperatures of 20°-100° C. for 2-48 hoursis the preferred method.

Ethers (132) can be prepared from the alcohols (125), as shown in Scheme24, equation c), by treatment of (125) in a solvent such as DMF or DMSOwith potassium t-butoxide or sodium hydride followed by treatment withR⁴ L at 25° C. for 1-20 hours, where L is a halogen, mesylate ortosylate group. Alternatively, treatment of chlorides (126) with 1-3equivalents of R⁴ OM where M is sodium or potassium, for 2-10 hours at25° C., either in R⁴ OH as solvent or in a polar solvent such as DMFwill also give ethers (132). Such ethers (132) may also be prepared, forexample, by heating (125) for 3-15 hours at 60°-160° C. in R⁴ OHcontaining an inorganic acid such as hydrochloric or sulfuric acids.

As shown by Scheme 24, equation d), amides (133) may be prepared fromcarboxylic acids (128) through a variety of methods familiar to oneskilled in the art and as described previously (Scheme 2).

Scheme 25, equation a), shows how amines (134) may be obtained fromchlorides (126) by displacement with ammonia, or through a Gabrielsynthesis, or by displacement with sodium azide followed by reduction asdescribed earlier (Scheme 14). Access to homologous amines (134) may begained by reduction of nitriles (127) with, for example, metal hydridereagents like LiAlH₄ or via catalytic hydrogenation. Such amines (134)may be converted to sulfonamides (135) and carbamates (136), usingstandard procedures familiar to one skilled in the art.

Scheme 25, equation b), illustrates the preparation of thioethers (137)from chlorides (126) by displacement with the sodium or potassium saltof alkyl mercaptans. Sulfides (137) may be oxidized to the correspondingsulfoxide and sulfone derivatives (138) with a variety of oxidants, forexample, hydrogen peroxide, sodium periodate, t-butyl hypochlorite,sodium perborate, or peroxycarboxylic acids, S. Palai, The Chemistry ofFunctional Groups, Supplement E, pt. 1, pp. 539-608, Wiley, New York(1980).

Alternative introduction of sulfur may be achieved by conversion of thehydroxyl group of 139 to thiolacetic acid derivatives (141), J. Y.Gauthier, Tetrahedron Lett. 15 (1986), and, subsequently, to mercaptans(142) by hydrolysis as illustrated in Scheme 25, equation c).

Also as shown in Scheme 25, equation c), the hydroxyl group can beconverted to its corresponding fluoro compound (140) by variousfluorinating agents such as DAST.

The nitriles (127) can be converted into the corresponding tetrazolederivatives (143) by a variety of methods using hydrazoic acid as shownby Scheme 25, equation d). For example, the nitrile can be heated withsodium azide and ammonium chloride in DMF at temperatures between 30° C.and reflux for 1-10 days, J. P. Hurwitz and A. J. Tomson, J. Org. Chem.,26, 3392 (1961). Preferably, the tetrazole is prepared by the2,3-dipolar cycloaddition of trialkyltin or triaryltin azides to theappropriately substituted nitrile as described previously in Scheme 7.

As shown by Scheme 26, equation a), the hydroxymethyl group of (125) canbe oxidized to the corresponding aldehydes (144) using a mild oxidant,such as manganese dioxide or cerric ammonium nitrate. Such aldehydes mayundergo typical chain-extensions via the Wittig and Wittig-Horner-Emmonsreactions to give alkenyl compounds such as 146 directly or react withGrignard and lithium reagents to give alcohols (145). These alcohols mayundergo dehydration to the corresponding alkenyl compounds (146) usingstandard methods, for example, by first converting such alcohols (145)to the corresponding mesylate, tosylate or halide derivatives followedby elimination using an appropriate base such as DBU, triethylamine, orpotassium t-butoxide.

Alternative access to alkenyl-substituted heterocycles may be gained viathe corresponding alkylheterocycles (147) as illustrated for Scheme 26,equation b). Free-radical bromination of (147) by UV-irradiation for 1-4hours in the presence of N-bromosuccinimide in an inert solvent such ascarbon tetrachloride at 25° C. gives bromides (148). Treatment of theseintermediates (148) with an appropriate base such as DBU, triethylamine,or potassium t-butoxide, affords (predominantly or exclusively) thetransalkenylheterocycles (149). The corresponding cis-alkenylderivatives (151) may be prepared as described above (for 146) or fromthe trans-alkenyl compounds (149) by oxidative cleavage with osmiumtetroxide and sodium periodate to give aldehydes (150) followed byWittig chemistry. ##STR26##

Described herein are general methods for the preparation of specificfunctional groups on R¹ and R² claimed in this invention. As before, itis understood by those skilled in the art of organic synthesis that allfunctionality present must be consistent with the chemicaltransformation proposed.

The compounds of this invention and their preparation can be understoodfurther by the following examples, but should not constitute alimitation thereof.

EXAMPLE 1 Part A: Methyl 4'-azidomethylbiphenyl-2-carboxylate

To a solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (5.0 g,16.4 mmol) in DMF (40 ml) was added sodium azide (2.7 g, 41 mmol). Themixture was stirred overnight at room temperature, filtered, and thefiltrate was partitioned between water and ethyl acetate (100 ml). Theaqueous phase was extracted once more with ethyl acetate (100 ml) andthe combined organic phase was washed with water (3×100 ml) andsaturated aqueous sodium chloride (100 ml) before being dried (MgSO₄),filtered and concentrated to an oily residue (3.9 g) which was used inthe subsequent reaction without further purification: NMR (200 MHz;CDCl₃, TMS) δ:7.9-7.2 (m,8H), 4.37 (s,2H), and 3.60 (s,3H).

Part B: 4- and5-Butyl-1-[(2'-carbo-methoxybiphenyl-4-yl)methyl]-1,2,3-triazoles

A solution of methyl 4'-azidomethylbiphenyl-2-carboxylate (2.0 g, 9.7mmol) and 1-hexyne (10 ml) was refluxed (70°-71° C.) for 2 days.Concentration in vacuo gave 3.2 g of a yellow oily residue from whichboth isomers could be isolated via flash chromatography with neutralalumina (150 g, Activity I; 20% EtOAc/hexanes).

Isolated was 0.58 g of the 4-isomer (high R_(f)) and 0.47 g of the5-isomer (low R_(f)); NMR (4-isomer; 200 MHz; CDCl₃, TMS) δ:7.86-7.20(m,9H), 5.55(s,2H), 3.63(s,3H), 2.72(t,J=7 Hz,2H), 1.69-1.61(m,2H),1.43-1.26(m,2H), 0.92(t,J=7.5 Hz,3H).

NMR(5-isomer; 200 MHz; CDCl₃, TMS) identical with the 4-isomer exceptthe triplet at 2.72 ppm was shifted to 2.54 ppm.

Part C: 4-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,3-triazole

To a solution of 480 mg (1.37 mmol) of4-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,3-triazole inmethanol (20 ml) was added 4N NaOH (20 ml). The resulting slurry wasstirred while being refluxed for 2-6 hours (or until a homogeneoussolution resulted). The methanol was removed by rotary evaporation andthe residue was diluted to a volume of 35 ml with water. Titration to pH4 with dilute HCl gave a sticky precipitate which was extracted intoethyl acetate; the organic layer was dried over MgSO₄, filtered andconcentrated to leave 438 mg of a white solid; m.p. 90°-95° C.

NMR (200 MHz; CDCl₃, CD₃ OD,TMS) δ:7.93-7.24(m,9H), 5.52(s,2H),2.69(t,J=7.5 Hz,2H), 1.67-1.59(m,2H), 1.42-1.37(m,2H), 0.92(t,J=7Hz,3H).

EXAMPLE 2 5-Butyl-1-[2'-carboxybiphenyl-4-yl)-methyl]-1,2,3-triazole

From 5-butyl-1-[2'-carboxymethylbiphenyl-4-yl)-methyl]-1,2,3-triazole(458 mg, 1.3 mmol) was obtained 363 mg of the title compound using theprocedure of Example 1, Part C; m.p. 50°-56° C.

NMR (200 MHz; CDCl₃, TMS) δ:7.96-7.13(m,9H), 5.53(s,2H), 2.52(t,J=7Hz,2H), 1.60-1.45(m,2H), 1.40-1.25(m,2H), 0.85(t,J=7 Hz,3H).

EXAMPLE 3 Part A:4'-Azidomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl

This compound was prepared according to the procedure of Example 1, PartA. From 4'-bromomethyl-2-(1-triphenylmethyl-2-tetrazol-5-yl)biphenyl(5.0 g, 9 mmol) was obtained 4.5 g of the title compound as a whitesolid.

NMR (200 MHz; CDCl₃,TMS) δ:7.93-6.88(m,23H), 4.24(s,2H).

Part B: 4- and5-Butyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]-1,2,3-triazoles

These compounds were prepared according to the procedure of Example 1,Part B. From 4'-azidomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl(4.5 g, 8.7 mmol) was obtained 5.4 g of the crude isomers which werepurified by chromatography on silica gel (300 g, 50% Et₂ O/hexanes).

There was obtained 1.81 g of the 4-butyl isomer: NMR (200 MHz, CDCl₃,TMS) δ:8.0-6.87(m,24H), 5.35(s,2H), 2.60(t,J=7.5 Hz,2H),1.59-1.51(m,2H), 1.38-1.27(m,2H), 0.89(t,J=7 Hz,3H).

There was also obtained 1.49 g of the 5-butyl isomer which displayed anearly identical NMR with the exception of minor changes in thesplitting pattern in the aromatic region and a shift in the triplet at2.60 ppm to 2.40 ppm.

Part C:4-Butyl-1-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl-1,2,3-triazoles

To a slurry of4-butyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl-1,2,3-triazole(1.45 g, 2.4 mmol) in water (15 ml) was added dropwise a solution oftrifluoroacetic acid in water (1/1, 30 ml) over several minutes. Theslurry was further further stirred for 30 minutes before being madealkaline with 4N NaOH (50 ml). The mixture was extracted twice withether (100 ml) and the aqueous phase was acidified to pH 4 with 4N HClto give a white precipitate which was suction filtered, washed withwater and hexanes and dried under vacuum to give 754 mg (87%) of a whitesolid : NMR (200 MHz; CDCl₃,TMS) δ:7.91-7.00(m,9H), 5.40(s,2H),2.53(t,J=7 Hz,2H), 1.56-1.48(m,2H), 1.33-1.22(m,2H), 0.86(t,J=7 Hz,3H).

EXAMPLE 45-Butyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3-triazole

This compound was obtained using the same procedure of Example 3, PartC.

In this case, acidification of the aqueous phase resulted in a gummyprecipitate which could be extracted into ethyl acetate. The organiclayer was dried (MgSO₄), filtered and concentrated to give the titlecompound as a white solid. From5-butyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]-1,2,3-triazole(1.4 g, 2.3 mmol) was obtained 600 mg (71%) of the title compound. NMR(200 MHz; CDCl₃,CD₃ OD,TMS) δ:7.78-7.06(m,9H), 5.47(s,2H),2.60-2.52(t,J=8 Hz,2H), 1.65-1.50(m,2H), 1.41-1.30(m,2H), 0.91(t,J=7Hz,3H).

The 1,2,3-triazoles listed in Table I are examples of compounds of thisinvention which were prepared or could be prepared by the procedures ofExamples 1-4 or by procedures previously described herein.

                                      TABLE 1                                     __________________________________________________________________________    1,2,3-TRIAZOLES                                                                ##STR27##                                                                    Ex.                                                                           No.                                                                              R.sup.1    R.sup.2    R.sub.3                                                                             R.sup.5                                                                            A   m.p. (°C.)                     __________________________________________________________________________     1 H          n-butyl    CO.sub.2 H                                                                          H    Single                                                                            90-95                                                                     bond                                       2  -n-butyl  H          CO.sub.2 H                                                                          H    Single                                                                            50-56                                                                     bond                                       3 H           -n-butyl  CN.sub.4 H                                                                          H    Single                                                                            133-136                                                                   bond                                       4  -n-butyl  H          CN.sub.4 H                                                                          H    Single                                                                            (Amorphous)                                                               bond                                       5 H          C.sub.2 H.sub.5                                                                          CO.sub.2 H                                                                          H    Single                                                                        bond                                       6 C.sub.2 H.sub.5                                                                          H          CO.sub.2 H                                                                          H    Single                                                                        bond                                       7 H           -n-propyl CO.sub.2 H                                                                          H    Single                                                                        bond                                       8  -n-propyl H          CO.sub.2 H                                                                          H    Single                                                                        bond                                       9 H           -n-C.sub.5 H.sub.11                                                                     CO.sub.2 H                                                                          H    CO                                        10  -n-C.sub.5 H.sub.11                                                                     H          CO.sub.2 H                                                                          H    CO                                        11 H           -n-C.sub.6 H.sub.13                                                                     CO.sub.2 H                                                                          H    CO                                        12  -n-C.sub.6 H.sub.13                                                                     H          CO.sub.2 H                                                                          H    CO                                        13 H          CHCHCH.sub.3                                                                             NHSO.sub.2 CF.sub.3                                                                 H    OCH.sub.2                                 14 CHCHCH.sub.3                                                                             H          NHSO.sub.2 CF.sub.3                                                                 H    OCH.sub.2                                 15 H          CHCHCH.sub.2 CH.sub.3                                                                    NHSO.sub.2 CF.sub.3                                                                 H    OCH.sub.2                                 16 CHCHCH.sub.2 CH.sub.3                                                                    H          NHSO.sub.2 CF.sub.3                                                                 H    OCH.sub.2                                 17 H          CHCH(CH.sub.2).sub.2 CH.sub.3                                                            NHSO.sub.2 CF.sub.3                                                                 H    Single                                                                        bond                                      18 CHCH(CH.sub.2).sub.2 CH.sub.3                                                            H          NHSO.sub.2 CF.sub.3                                                                 H    Single                                                                        bond                                      19 H          CHCH(CH.sub. 2).sub.3 CH.sub.3                                                           NHSO.sub.2 CF.sub.3                                                                 H    Single                                                                        bond                                      20 CHCH(CH.sub.2).sub.3 CH.sub.3                                                            H          NHSO.sub.2 CF.sub.3                                                                 H    Single                                                                        bond                                      21 H          CCCH.sub.3 CO.sub.2 H                                                                          H    O                                         22 CCCH.sub.3 H          CO.sub.2 H                                                                          H    O                                         23 H          CCCH.sub.2 CH.sub.3                                                                      CO.sub.2 H                                                                          H    O                                         24 CCCH.sub.2 CH.sub.3                                                                      H          CO.sub.2 H                                                                          H    O                                         25 H          CC(CH.sub.2).sub.2 CH.sub.3                                                              CO.sub.2 H                                                                          H    O                                         26 CC(CH.sub.2).sub.2 CH.sub.3                                                              H          CO.sub.2 H                                                                          H    O                                         27 H          CC(CH.sub.2).sub.3 CH.sub.3                                                              CO.sub.2 H                                                                          H    O                                         28 CC(CH.sub.2 ).sub.3 CH.sub.3                                                             H          CO.sub.2 H                                                                          H    O                                         29 H          CH.sub.2 OH                                                                              CO.sub.2 H                                                                          H    Single                                                                        bond                                      30 CH.sub.2 OH                                                                              H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      31 H          (CH.sub.2).sub.2 OCH.sub.3                                                               CO.sub.2 H                                                                          H    Single                                                                        bond                                      32 (CH.sub.2).sub.2 OCH.sub.3                                                               H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      33 H          (CH.sub.2).sub.3 OCH.sub.3                                                               CO.sub.2 H                                                                          H    Single                                                                        bond                                      34 (CH.sub.2).sub.3 OCH.sub.3                                                               H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      35 H          (CH.sub.2).sub.4 OCH.sub.3                                                               CO.sub.2 H                                                                          H    Single                                                                        bond                                      36 (CH.sub.2).sub.4 OCH.sub.3                                                               H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      37 H          (CH.sub.2).sub.5 OCH.sub.3                                                               CO.sub.2 H                                                                          H    Single                                                                        bond                                      38 (CH.sub.2).sub.5 OCH.sub.3                                                               H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      39 H          (CH.sub.2).sub.6 OCH.sub.3                                                               CO.sub.2 H                                                                          H    Single                                                                        bond                                      40 (CH.sub.2).sub.6 OCH.sub.3                                                               H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      41 H          CH.sub.2 OCH.sub.2 CH.sub.3                                                              CO.sub.2 H                                                                          H    Single                                                                        bond                                      42 CH.sub.2 OCH.sub.2 CH.sub.3                                                              H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      43 H          CH.sub.2 O(CH.sub.2).sub.2 CH.sub.3                                                      CO.sub.2 H                                                                          H    Single                                                                        bond                                      44 CH.sub.2 O(CH.sub.2).sub.2 CH.sub.3                                                      H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      45 H          CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                      CO.sub.2 H                                                                          H    Single                                                                        bond                                      46 CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                      H          CO.sub.2 H                                                                          H    Single                                                                        bond                                      47 H           -n-propyl CO.sub.2 H                                                                          CH.sub.3                                                                           NHCO                                      48  -n-propyl H          CO.sub.2 H                                                                          CH.sub.3                                                                           NHCO                                      49 H           -n-propyl CO.sub.2 H                                                                          Et   NHCO                                      50  -n-propyl H          CO.sub.2 H                                                                          Et   NHCO                                      51 H           -n-propyl CO.sub.2 H                                                                           .sub.-i-propyl                                                                    NHCO                                      52  -n-propyl H          CO.sub.2 H                                                                           .sub.-i-propyl                                                                    NHCO                                      53 H           -n-propyl CO.sub.2 H                                                                          s-butyl                                                                            NHCO                                      54  -n-propyl H          CO.sub.2 H                                                                          s-butyl                                                                            NHCO                                      55 H           -n-propyl CO.sub.2 H                                                                          OCH.sub.3                                                                          NHCO                                      56  -n-propyl H          CO.sub.2 H                                                                          OCH.sub.3                                                                          NHCO                                      57 H           -n-propyl CO.sub.2 H                                                                          F    NHCO                                      58  -n-propyl H          CO.sub.2 H                                                                          F    NHCO                                      59 H           -n-propyl NHSO.sub.2 CF.sub.3                                                                 Cl   NHCO                                      60  -n-propyl H          NHSO.sub.2 CF.sub.3                                                                 Cl   NHCO                                      61 H           -n-propyl NHSO.sub.2 CF.sub.3                                                                 Br   NHCO                                      62  -n-propyl H          NHSO.sub.2 CF.sub.3                                                                 Br   NHCO                                      63 H           -n-propyl NHSO.sub.2 CF.sub.3                                                                 I    NHCO                                      64  -n-propyl H          NHSO.sub.2 CF.sub.3                                                                 I    NHCO                                      65 H           -n-propyl CO.sub.2 H                                                                          NO.sub. 2                                                                          NHCO                                      66  -n-propyl H          CO.sub.2 H                                                                          NO.sub.2                                                                           NHCO                                      __________________________________________________________________________

EXAMPLE 67 Part A: Methyl 4'-aminomethylbiphenyl-2-carboxylatehydrochloride

A mixture of methyl 4'-azidomethylbiphenyl-2-carboxylate (111 g, 0.42mol; see Part A, Ex. 1) and 5% Pd on carbon (20 g) in methanol (1 L) wasplaced in a Parr apparatus under 50 psi H₂ atmosphere overnight at roomtemperature. The mixture was filtered through Celite and the filtratewas concentrated to a yellow viscous residue (88 g). This crude aminewas dissolved in ethyl acetate (500 ml), cooled to 0° C. and titratedwith a 0° C. solution of ethyl acetate saturated with hydrogen chlorideto completion of precipitation (ca. 110 ml).

The precipitate was collected by vacuum filtration and was washed withethyl acetate, hexanes and dried under vacuum to give 48.5 g (42%); m.p.200°-203° C.

NMR (200 MHz; CDCl₃, CD₃ OD,TMS) δ:7.90-7.25(m,8H), 4.15(s,2H),4.10-3.80(br,3H; exchanges D₂ O), 3.55(s,3H).

The corresponding nitrile was prepared similarly. From4'-azidomethylbiphenyl-2-nitrile (22.8 g, 97.3 mmol); see Ex. 1, Part A)was obtained the corresponding amine hydrochloride (15.4 g; 68%); m.p.230° C. (dec.).

NMR (200 MHz; CDCl₃, CD₃ OD,TMS) δ:7.81-7.47(m,8H), 4.19(s,2H),4.0(br,3H; exchanges D₂ O).

Part B:3-Butyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole

A solution of triethyl orthovalerate (3.3 g, 16.2 mmol), methoxyacetylhydrazide (1.7 g, 16.2 mmol) and DBU (1.8 g, 11.9 mmol) in xylenes (50ml) was refluxed for 2 hrs and cooled to room temperature, whereuponmethyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.0mmol) was added. The reaction was brought back to reflux for a further24 h. After being cooled to room temperature, the mixture was dilutedwith ethyl acetate (150 ml) and washed with water (100 ml), saturatedaqueous sodium chloride and dried (MgSO₄). Filtration and evaporation ofsolvents gave 4.8 g of a yellow oil which was purified by flashchromatography on silica gel (150 g, 5-10% EtOAc/hexane) to afford 3.4 g(78%) of the title compound as a yellow viscous oil.

NMR (200 MHz, CDCl₃,TMS) δ:7.87-7.05(m,8H), 5.25(s,2H), 4.56(s,2H),3.67(s,3H), 3.37(s,3H), 2.68(t,J=8 Hz,2H), 1.73(m,2H), 1.38(m,2H),0.90(t,J=9 Hz,3H).

Part C:3-Butyl-5-methoxymethyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,4-triazole

Hydrolysis of the 1,2,4-triazole esters was carried out in the samefashion as for the 1,2,3-triazoles as described in Example 1, Part C.

From3-butyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole(273 mg, 0.69 mmol) was obtained 218 mg (83%) of the title compound as awhite solid; m.p. 229°-232° C. (dec.).

NMR (200 MHz,CDCl₃,CD₃ OD,TMS) δ:7.90-7.04(m,8H), 5.24(s,2H),4.50(s,2H), 3.34(s,3H), 2.69(t,J=8 Hz,2H), 1.67(m,2H), 1.37(m,2H),0.90(t,J=7 Hz,3H).

EXAMPLE 68 Part A:3-Butyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to the method described in Example67, Part B.

From triethyl orthoformate (2.7 ml, 16.2 mmol), valeryl hydrazide (1.9 g16.2 mmol), DBU (1.8 ml, 11.9 mmol) and methyl4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol) inrefluxing xylenes (50 ml) was obtained 2.14 g (56%) of the titlecompound as a pale yellow oil following flash chromatography.

NMR (200 MHz, CDCl₃,TMS) δ:8.10(s,1H), 7.89-7.11(m,8H), 5.14(s,2H),3.66(s,3H), 2.71(t,J=7 Hz,2H), 1.78-1.66(m,2H), 1.46-1.34(m,2H),0.92(t,J=7 Hz,3H).

Part B: 3-Butyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to the method described for Example1, Part C.

From 3-butyl-4-[(2'-carbomethoxybiphenyl-4-yl)-methyl]-1,2,4-triazole(308 mg, 0.88 mmol) was obtained 219 mg (74%) of the title compound as awhite solid; m.p. 199°-201° C. (dec.).

NMR (200 MHz;CDCl₃,CD₃ OD,TMS) δ:8.10(s,1H), 7.95-7.12(m,8H),5.11(s,2H), 2.72(t,J=8HZ,2H), 1.72-1.68(m,2H), 0.92(t,J=7 Hz,3H).

EXAMPLE 69 Part A:3-Methoxymethyl-5-propyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to the method described for Example67, Part B.

From triethyl orthobutyrate (3.1 g, 16.2 mmol) methoxyacetyl hydrazide(1.7 g, 16.2 mmol) DBU (1.8 ml, 11.9 mmol) and methyl4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol) inrefluxing xylenes (50 ml) was obtained 2.3 g (56%) of the title compoundas a colorless oil following flash chromatography.

NMR (200 MHz;CDCl₃,TMS) δ:7.88-7.04(m,8H), 5.25(s,2H), 4.56(s,2H),3.65(s,3H), 3.34(s,3H), 2.66(t,J=7 Hz,2H), 1.78(m,2H), 0.98(t,J=7Hz,3H).

Part B:3-Methoxymethyl-5-propyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,4-triazol

This compound was prepared according to Example 1, Part C.

From3-methoxymethyl-5-propyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole(2.1 g, 5.5 mmol) was obtained 1.84 g (91%) of the title compound as awhite solid, m.p. 225°-227.5° C. (dec.).

NMR (200 MHz; CDCl₃, CD₃ OD,TMS) δ:7.93-7.03(m,8H), 5.24(s,2H),4.51(s,2H), 3.33(s,3H), 2.65(t,J=7 Hz,2H), 1.73(m,2H), 0.96(t,J=7Hz,3H).

EXAMPLE 70 Part A:3-Ethyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to Example 67, Part B.

From triethyl orthopropionate (2.86 g, 16.2 mmol),methoxyacetylhydrazide (1.7 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) andmethyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8mmol) in refluxing xylenes (50 ml) was obtained 2.4 g (60%) of the titlecompound as a pale yellow oil following flash chromatography.

NMR (200 MHz, CDCl₃,TMS) δ:7.88-7.05(m,8H), 5.24(s,2H), 4.58(s,2H),3.65(s,3H), 3.35(s,3H), 2.67(q,J=7 Hz,2H), 1.32(t,J=7 Hz,3H).

Part B:3-Ethyl-5-methoxymethyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,4-triazole

From3-ethyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole(2.2 g, 6.0 mmol) was obtained 1.81 g (86%) of the title compound as awhite solid; m.p. 234°-235.5° C. (dec.).

NMR (200 MHz;CDCl₃,CD₃ OD,TMS) δ:7.93-7.04(m,8H), 5.24(s,2H),4.53(s,2H), 3.34(s,3H), 2.69(q,J=7 Hz,2H), 1.29(t,J=7 Hz, 3H).

EXAMPLE 71 Part A:3,5-Dibutyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to the methods described forExample 67, Part B.

From triethyl orthovalerate (3.3 g, 16.2 mmol), valeryl hydrazide (1.9g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) and methyl4'-aminomethylbiphenyl-2-carboxylate (3.0 g, 10.8 mmol) in refluxingxylenes (50 ml) was obtained 2.5 g (57%) of the title compound as a paleyellow oil.

NMR (200 MHz;CDCl₃,TMS) δ:7.88-6.98(m,8H), 5.11(s,2H), 3.65(s,3H),2.66(t,J=7 Hz,4H), 1.79-1.63(m,4H), 1.48-1.33(m,4H), 0.89(t,J=7 Hz,6H).

Part B: 3,5-Dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to the methods described forExample 1, Part C.

From 3,5-dibutyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole(2,4 g, 5.92 mmol) was obtained 1.88 g (81%) of the title compound as awhite solid; m.p. 207°-209° C.

NMR (200 MHz;CDCl₃,CD₃ OD,TMS) δ:7.93-6.96(m,8H), 5.12(s,2H),4.06(s,2H), 2.66(t,J=7 Hz,4H), 1.74-1.59(m,4H), 1.45-1.27(m,4H),0.89(t,J=7 Hz,6H).

EXAMPLE 72 Part A:3-Methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-1,2,4-triazole

This compound was prepared according to the methods described forExample 67, Part B.

From triethyl orthobutyrate (2.3 g, 12.3 mmol) methoxyacetyl hydrazide(1.4 g, 12.3 mmol), DBU (1.4 ml, 8.9 mmol) and4'-aminomethylbiphenyl-2-nitrile (2.0 g, 8.2 mmol) in refluxing xylenes(50 ml) was obtained 1.6 g (57%) of the title compound, as a viscous oilwhich slowly crystallized upon standing at room temperature.

NMR (200 MHz;CDCl₃,TMS) δ:7.80-7.12(m,8H), 5.28(s,2H), 4.56(s,2H),3.34(s,3H), 2.65(t,J=7 Hz,2H), 1.78(m,2H), 0.99(t,J=7 Hz,3H).

Part B:3-Methoxymethyl-5-propyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,4-triazole

To a solution of3-methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-1,2,4-triazole(1.5 g, 4.33 mmol) in DMF (35 ml) was added sodium azide (NaN₃, 0.84 g,13 mmol) and ammonium chloride (NH₄ Cl, 0.69 g, 13 mmol). The mixturewas stirred at 100° C. for four days whereupon an additional 0.3 g NaN₃and 0.23 g NH₄ Cl were added. Stirring was continued 2 days further at100° C. The solvent was removed (rotary evaporation) and the residue waspartitioned between ethyl acetate and water (100 ml ea). The organicphase was dried (MgSO₄), filtered and concentrated to a viscous lightbrown oil (1.5 g) which was purified by flash chromatography on silicagel to give 350 mg (21%) of an off-white solid; m.p. 201°-205° C.(dec.).

NMR (200 MHz;CDCl₃,CD₃ OD,TMS) δ:, 7.75-6.93(m,8H), 5.19(s,2H),4.47(s,2H), 3.31(s,3H), 2.62(t,J=7 Hz,2H), 1.78-1.66(m,2H), 0.96(t,J=7Hz,3H).

Table 2 lists examples of 1,2,4-triazoles of this invention which wereprepared or could be prepared by the procedures of examples 67-72 or byprocedures previously described.

                                      TABLE 2                                     __________________________________________________________________________    1,2,4-TRIAZOLES                                                                ##STR28##                                                                    Ex.                                                                           No. R.sup.1  R.sup.2      R.sub.3                                                                             R.sup.5                                                                           A     m.p. (°C.)                   __________________________________________________________________________    67   -n-butyl                                                                              CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                                                                         229-231 (dec.)                      68   -n-butyl                                                                              H            CO.sub.2 H                                                                          H   Single bond                                                                         199-201 (dec.)                      69   -n-propyl                                                                             CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                                                                         225-227.5 (dec.)                    70  C.sub.2 H.sub.5                                                                        CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                                                                         234-235.5 (dec.)                    71   -n-butyl                                                                               -n-butyl    CO.sub.2 H                                                                          H   Single bond                                                                         207-209 (dec.)                      72   -n-propyl                                                                             CH.sub.2 OCH.sub.3                                                                         CN.sub.4 H                                                                          H   Single bond                                                                         201-205 (dec.)                      73   -n-propyl                                                                             CH.sub.2 OH  CN.sub.4 H                                                                          H   Single bond                               74   -n-propyl                                                                             CHO          CN.sub.4 H                                                                          H   Single bond                               75   -n-propyl                                                                             CO.sub.2 CH.sub.3                                                                          CN.sub.4 H                                                                          H   Single bond                               76   -n-propyl                                                                             CO.sub.2 C.sub.2 H.sub.5                                                                   CN.sub.4 H                                                                          H   Single bond                               77   -n-propyl                                                                             CO.sub.2 - -n-C.sub.3 H.sub.7                                                              CN.sub.4 H                                                                          H   Single bond                               78   -n-propyl                                                                             CO.sub.2 - -n-C.sub.4 H.sub.9                                                              CN.sub.4 H                                                                          H   Single bond                               79   -n-propyl                                                                             CO.sub.2 - -n-C.sub.5 H.sub.11                                                             CN.sub.4 H                                                                          H   Single bond                               80   -n-propyl                                                                             CO.sub.2 - -c-C.sub.3 H.sub.5                                                              CN.sub.4 H                                                                          H   Single bond                               81   -n-propyl                                                                             CO.sub.2 - -c-C.sub.4 H.sub.7                                                              CN.sub.4 H                                                                          H   Single bond                               82   -n-propyl                                                                             CO.sub.2 - -c-C.sub.5 H.sub.9                                                              CN.sub.4 H                                                                          H   Single bond                               83   - n-propyl                                                                            CO.sub.2 - -c-C.sub.6 H.sub.11                                                             CN.sub.4 H                                                                          H   Single bond                               84   -n-propyl                                                                             CO.sub.2 Ph  CN.sub.4 H                                                                          H   Single bond                               85   -n-propyl                                                                             CO.sub.2 CH.sub.2 Ph                                                                       CN.sub.4 H                                                                          H   Single bond                               86   -n-propyl                                                                             CH.sub.2 COPh                                                                              CO.sub.2 H                                                                          H   Single bond                               87   -n-propyl                                                                             CH.sub.2 COCH.sub.2 Ph                                                                     CO.sub.2 H                                                                          H   Single bond                               88   -n-propyl                                                                             CH.sub.2 CO(CH.sub.2).sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                               89   -n-propyl                                                                             CH.sub.2 CO(CH.sub.2).sub.3 Ph                                                             CO.sub.2 H                                                                          H   Single bond                               90   -n-propyl                                                                             (CH.sub.2).sub.4 COCH.sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                               91   -n-propyl                                                                             (CH.sub.2).sub.5 COCH.sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                               92   -n-propyl                                                                             (CH.sub.2).sub.6 COCH.sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                               93   -n-propyl                                                                             CONH.sub.2   CO.sub.2 H                                                                          H   Single bond                               94   -n-propyl                                                                             CONHCH.sub.3 CO.sub.2 H                                                                          H   Single bond                               95   -n-propyl                                                                             CON(CH.sub.3).sub.2                                                                        CO.sub.2 H                                                                          H   Single bond                               96   -n-propyl                                                                             CONHEt       CO.sub.2 H                                                                          H   Single bond                               97   -n-propyl                                                                             CONH- -n-Pr  CO.sub.2 H                                                                          H   Single bond                               98   -n-propyl                                                                             CONH- -n-Bu  CO.sub.2 H                                                                          H   Single bond                               99   -n-propyl                                                                             CONHPh       CO.sub.2 H                                                                          H   Single bond                               100  -n-propyl                                                                             CONHCH.sub.2 Ph                                                                            CO.sub.2 H                                                                          H   Single bond                               101  -n-propyl                                                                              ##STR29##   CO.sub.2 H                                                                          H   Single bond                               102  -n-propyl                                                                              ##STR30##   CO.sub.2 H                                                                          H   Single bond                               103  -n-propyl                                                                              ##STR31##   CO.sub.2 H                                                                          H   Single bond                               104  -n-propyl                                                                              ##STR32##   CO.sub.2 H                                                                          H   Single bond                               105  -n-propyl                                                                              ##STR33##   CO.sub.2 H                                                                          H   Single bond                               106  -n-propyl                                                                              ##STR34##   CO.sub.2 H                                                                          H   Single bond                               107  -n-propyl                                                                              ##STR35##   CO.sub.2 H                                                                          H   Single bond                               108  -n-propyl                                                                              ##STR36##   CO.sub.2 H                                                                          H   Single bond                               109  -n-propyl                                                                              ##STR37##   CO.sub.2 H                                                                          H   Single bond                               110  -n-propyl                                                                              ##STR38##   CN.sub.4 H                                                                          H   Single bond                               111  -n-propyl                                                                             CH.sub.2 SCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                               112  -n-propyl                                                                              ##STR39##   CO.sub.2 H                                                                          H   Single bond                               113  -n-propyl                                                                              ##STR40##   CO.sub.2 H                                                                          H   Single bond                               114  -n-propyl                                                                             CHCHCH.sub.2 OH                                                                            CO.sub.2 H                                                                          H   Single bond                               115  -n-propyl                                                                             CHCHCH.sub.2 OCH.sub.3                                                                     CO.sub.2 H                                                                          H   Single bond                               116  -n-propyl                                                                             CHCHCH.sub.2 OC.sub.2 H.sub.5                                                              CO.sub.2 H                                                                          H   Single bond                               117  -n-propyl                                                                             CHCHCH.sub.2 O- -n-C.sub.3 H.sub.7                                                         CO.sub.2 H                                                                          H   Single bond                               118  -n-propyl                                                                             CHCHCH.sub.2 O- -n-C.sub.4 H.sub.9                                                         CO.sub.2 H                                                                          H   Single bond                               119  -n-propyl                                                                              ##STR41##   CO.sub.2 H                                                                          H   Single bond                               120  -n-propyl                                                                              ##STR42##   CO.sub.2 H                                                                          H   Single bond                               121  -n-propyl                                                                              ##STR43##   CO.sub.2 H                                                                          H   Single bond                               122  -n-propyl                                                                              ##STR44##   CO.sub. 2 H                                                                         H   Single bond                               123  -n-propyl                                                                              ##STR45##   CO.sub.2 H                                                                          H   Single bond                               124  -n-propyl                                                                              ##STR46##   CO.sub.2 H                                                                          H   Single bond                               125  -n-propyl                                                                             CO.sub.2 NHCO.sub.2 CH.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                               126  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 C.sub.2 H.sub.5                                                        CO.sub.2 H                                                                          H   Single bond                               127  -n-propyl                                                                             CH2NHCO.sub.2 - -n-C.sub.3 H.sub.7                                                         CO.sub.2 H                                                                          H   Single bond                               128  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 - -n-C.sub.4 H.sub.9                                                   CO.sub.2 H                                                                          H   Single bond                               129  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 - -n-C.sub.5 H.sub.11                                                  CO.sub.2 H                                                                          H   Single bond                               130  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 - -n-C.sub.6 H.sub.13                                                  CO.sub.2 H                                                                          H   Single bond                               131  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               132  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 CF.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                               133  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 CH.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                               134  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 CF.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                               135  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 C.sub.2 F.sub.5                                                        CO.sub.2 H                                                                          H   Single bond                               136  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 - -n-C.sub.3 F.sub.7                                                   CO.sub.2 H                                                                          H   Single bond                               137  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 - -n-C.sub.4 F.sub.9                                                   CO.sub.2 H                                                                          H   Single bond                               138  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 - -n-C.sub.5 F.sub.11                                                  CO.sub.2 H                                                                          H   Single bond                               139  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 - -n-C.sub.6 F.sub.13                                                  CO.sub.2 H                                                                          H   Single bond                               140  -n-propyl                                                                             CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               141  - n-propyl                                                                            CH.sub.2 F   CO.sub.2 H                                                                          H   Single bond                               142  -n-propyl                                                                             CH.sub.2 CN.sub.4 H                                                                        CO.sub.2 H                                                                          H   Single bond                               143  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 Ph                                                                     CO.sub.2 H                                                                          H   Single bond                               144  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 (CH.sub.2).sub.2 Ph                                                    CO.sub.2 H                                                                          H   Single bond                               145  -n-propyl                                                                             CH.sub.2 NHCO.sub.2 (CH.sub.2).sub.3 Ph                                                    CO.sub.2 H                                                                          H   Single bond                               146  -n-propyl                                                                             CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          NO.sub.2                                                                          NHCO                                      147  -n-propyl                                                                             CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          OCH.sub.3                                                                         NHCO                                      148  -n-propyl                                                                             CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          CH.sub.3                                                                          NHCO                                      149  -n-propyl                                                                             CO.sub.2 H   CO.sub.2 H                                                                          H   Single bond                               150 CH.sub.2 OH                                                                            H            CO.sub.2 H                                                                          H   Single bond                               151 CH.sub.2 OH                                                                             -n-C.sub.5 H.sub.11                                                                       CO.sub.2 H                                                                          H   Single bond                               152 CH.sub.2 OH                                                                             -n-C.sub.6 H.sub.13                                                                       CO.sub.2 H                                                                          F   NHCO                                      153 (CH.sub.2).sub. 2 OCH.sub.3                                                             -n-propyl   CO.sub.2 H                                                                          H   Single bond                               154 (CH.sub.2).sub.3 OCH.sub.3                                                              -n-propyl   CO.sub.2 H                                                                          H   Single bond                               155 (CH.sub.2).sub.4 OCH.sub.3                                                              -n-propyl   CO.sub.2 H                                                                          Cl  NHCO                                      156 (CH.sub.2).sub.5 OCH.sub.3                                                              -n-propyl   CO.sub.2 H                                                                          Br  NHCO                                      157 (CH.sub.2).sub.6 OCH.sub.3                                                              -n-propyl   NHSO.sub.2 CF.sub.3                                                                 I   NHCO                                      158 CH.sub.2 OCH.sub.2 CH.sub.3                                                             -n-propyl   CO.sub.2 H                                                                          H   O                                         159 CH.sub.2 O(CH.sub.2).sub.2 CH.sub.3                                                     -n-propyl   CO.sub.2 H                                                                          H   O                                         160 CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                     -n-propyl   CO.sub.2 H                                                                          H   O                                         161 CH.sub.2 OCH.sub.3                                                                     CHCHCH.sub.3 CO.sub.2 H                                                                          H   CO                                        162 CH.sub.2 OCH.sub.3                                                                     CHCHCH.sub.2 CH.sub.3                                                                      CO.sub.2 H                                                                          H   CO                                        163 CH.sub.2 OCH.sub.3                                                                     CHCH(CH.sub.2).sub.2 CH.sub.3                                                              CO.sub.2 H                                                                          H   CO                                        164 CH.sub.2 OCH.sub.3                                                                     CHCH(CH.sub.2).sub.3 CH.sub.3                                                              CO.sub.2 H                                                                          H   CO                                        165 CH.sub.2 OCH.sub.3                                                                     CCCH.sub.3   CO.sub.2 H                                                                          H   CO                                        166 CH.sub.2 OCH.sub.3                                                                     CCCH.sub.2 CH.sub.3                                                                        CO.sub.2 H                                                                          H   CO                                        167 CH.sub.2 OCH.sub.3                                                                     CC(CH.sub.2).sub.2 CH.sub.3                                                                CO.sub.2 H                                                                          H   CO                                        168 CH.sub.2 OCH.sub.3                                                                     CC(CH.sub.2).sub.3 CH.sub.3                                                                CO.sub.2 H                                                                          H   CO                                        169  -n-propyl                                                                             CO.sub.2 H   CO.sub.2 H                                                                          H   OCH.sub.2                                 __________________________________________________________________________

EXAMPLE 170 Part A: 1-Methoxy-2,4-octadione

To a solution of methyl methoxyacetate (20.8 g, 200 mmol) in toluene(250 ml) was added sodium ethoxide (7.5 g, 110 mmol) followed by2-hexanone (10 g, 100 mmol). The mixture was stirred overnight at roomtemperature, quenched with water (˜100 ml) and acidified to about pH 5with glacial acetic acid. The aqueous phase was extracted with ethylacetate (100 ml) and the combined organic phases were washed withsaturated brine before being dried (MgSO₄), filtered and concentratedunder medium vacuum (20 mm Hg, rotary evaporator) to leave 15.8 g of abrown liquid. Fractional distillation at 4 mm Hg gave the purifiedproduct, b.p. 111°-116° C. The yield was 7.2 g (42%) of a clear liquid.

NMR (200 MHz;CDCl₃,TMS) δ:5.79(s,1H), 3.99(s,2H), 3.43(s,3H), 2.33(t,J=7Hz,2H), 1.65-1.54(m,2H), 1.42-1.27(m,2H), 0.93(t,J=7 Hz, 3H).

Part B: 3(5)-Butyl-5(3)-methoxymethylpyrazole

To a solution of 1-methoxy-2,4-octadione (1.9 g, 11.0 mmol) in ethanol(20 ml) was added dropwise and with stirring a solution of hydrazinehydrate (0.8 g, 16.5 mmol) in ethanol (10 ml). Following 1 hour at roomtemperature, the mixture was refluxed 1 hour before being concentratedto an oily residue. This crude product was dissolved in CH₂ Cl₂, driedover MgSO₄, filtered and concentrated to leave 1.69 g (91%) of the titlecompound as a yellow-orange oil, used in subsequent transformationswithout further purification.

NMR (200 MHz;CDCl₃,TMS) δ:6.07(s,1H), 4.47(s,2H), 3.39(s,3H), 2.64(t,J=7Hz,2H), 1.63(m,2H), 1.39(m,2H), 0.92(t,7 Hz,3H).

Part C: 3-Methoxymethyl-5-butyl- and5-methoxymethyl-3-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazoles

To a solution of 3(5)-butyl-5(3)-methoxymethylpyrazole (0.86 g, 5.1mmol) in DMF (30 ml) was added NaH (141 mg, 6.2 mmol). The mixture wasstirred 15 minutes and methyl 4'-bromomethylbiphenyl-2-carboxylate (1.87g, 6.1 mmol) was added as a solution in DMF (5 ml). The mixture wasstirred overnight at room temperature before being poured into aseparatory funnel containing ethyl acetate (100 ml) and water (100 ml).The aqueous phase was extracted once more with ethyl acetate and thecombined organic phase was washed thrice with water (100 ml) beforebeing dried (MgSO₄), filtered and concentrated to leave 1.6 g of thecrude product as brown oil. The isomers were separated by flashchromatography on silica gel (65 g, 20% EtOAc/hexanes).

Isolated was 0.6 g of the 5-methoxymethyl-3-butyl isomer (high R_(f))and 0.8 g of the 3-methoxymethyl-5-butyl isomer (low R_(f)).

NMR (high R_(f) isomer; 200 MHz;CDCl₃,TMS) δ:7.82-7.12(m,8H),6.08(s,1H), 5.37(s,2H), 4.33(s,2H), 3.62(s,3H), 3.29(s,3H), 2.63(t,J=7Hz,2H), 1.62(m,2H), 1.39(m,2H), 0.93(t,J=7 Hz,3H).

NMR (low R_(f) isomer; 200 MHz;CDCl₃,TMS) δ:7.82-7.06(m,8H), 6.13(s,1H),5.32(s,2H), 4.46(s,2H), 3.61(s,3H), 3.41(s,3H), 2.51(t,J=7 Hz,2H),1.56(m,2H), 1.33(m,2H), 0.88(t,J=7 Hz,3H).

Part D:5-Methoxymethyl-3-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

Hydrolysis of this ester was effected via the method described inExample 1, Part C.

From5-methoxymethyl-3-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazole(500 mg, 1.28 mmol) was obtained 390 mg (80%) of the corresponding titlecompound as a light yellow powder; m.p. 129°-134° C.

NMR (200 MHz;CDCl₃,TMS) δ:7.93-7.10(m,8H), 6.04(s,1H), 5.15(s,2H),4.31(s,2H), 3.28(s,3H), 2.66(t,J=7 Hz,2H), 1.65-1.53(m,2H),1.42-1.31(m,2H), 0.92(t,J=7 Hz,3H).

EXAMPLE 1713-Methoxymethyl-5-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

Hydrolysis was performed in the same fashion as in Example 1, Part C.

From3-methoxymethyl-5-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-pyrazole(690 mg, 1.76 mmol) was obtained 540 mg (81%) of the title compound as alight yellow powder; m.p. 112°-119° C.

NMR (200 MHz;CDCl₃,TMS) δ:7.94-7.04 (m,8H), 6.10(s,1H), 5.14(s,2H),4.48(s,2H), 3.38(s,3H), 2.51(t,J=7 Hz,2H), 1.57-1.46(m,2H),1.38-1.27(m,2H), 0.87(t,J=7 Hz,3H).

EXAMPLE 172 Part A: 1-Methoxy-7-octen-2,4-dione

This diketone was prepared using the same procedure as described inExample 170, Part A.

From 5-hexen-2-one (19.6 g, 0.2 mol), methyl methoxyacetate (42 g, 0.4mol) and sodium methoxide (15.1 g, 0.22 mol) in toluene (500 ml) wasobtained 11.3 g (33%) of the title compound following fractionation at 4mm Hg; b.p. 111°-122° C.

NMR (200 MHz;CDCl₃,TMS) δ:5.79(m,2H), 5.10-4.99 (m,2H), 3.99(s,2H),3.43(s,3H), 2.43-2.33(m,4H).

Part B: 3(5)-But-3-enyl-5(3)-methoxymethylpyrazole

This compound was prepared using the same procedure in Example 170, PartB.

From 1-methoxy-7-octen-2,4-dione (5.0 g, 29.4 mmol) and hydrazinehydrate (2.2 g, 44.1 mmol) was obtained 3.4 g (69%) of the titlecompound as a yellow oil.

NMR (200 MHz;CDCl₃,TMS) δ:12-11(br,1H), 6.08(s,1H), 5.91-5.77(m,1H),5.09-4.97(m,2H), 4.48(s,2H), 3.37(s,3H), 2.77-2.70(t,J=7 Hz,2H),2.43-2.33(m,2H).

Part C: 3-Methoxymethyl-5-but-3-enyl and5-methoxymethyl-3-but-3-enyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazoles

These compounds could be prepared using the procedures described inExample 170, Part C. An alternative procedure could also be performedwith comparable results, whereby the NaH is replaced with an equivalentamount of K₂ CO₃ and the mixture heated to 65° C. for 18-24 hours.

From 3(5)-but-3-enyl-5(3)-methoxymethylpyrazole (2.0 g, 12.0 mmol),methyl 4'-bromomethylbiphenyl-2-carboxylate (4.8 g, 15.6 mmol), sodiumhydride (0.33 g, 14.3 mmol) or potassium carbonate (2.0 g, 14.3 mmol) inDMF (75 ml) was obtained 6 g of the crude title compounds which wereseparated by flash chromatography on silica gel (400 g; 10-20%EtOAc/hexanes).

Isolated was 1.22 g of the 5-methoxymethyl-3-but-3-enyl isomer (highR_(f)): NMR (200 MHz;CDCl₃,TMS) δ:7.83-7.12(m,8H), 6.10(s,1H),5.96-5.83(m,1H), 5.38(s,2H), 5.11-4.96(m,2H), 4.34(s,2H), 3.63(s,3H),3.29(s,3H), 2.74(t,J=8 Hz,2H), 2.47-2.40(m,2H).

Also isolated was 2.19 g of the 3-methoxymethyl-5-but-3-enyl isomer (lowR_(f)): NMR (200 MHz;CDCl₃,TMS) δ:7.83-7.07(m,8H), 6.15(s,1H),5.81-5.72(m,1H), 5.33(s,2H), 5.06-4.97(m,2H), 4.46(s,2H), 3.60(s,3H),3.42(s,3H), 2.62(t,J=7 Hz,2H), 2.38-2.04(m,2H).

Part D:3-Methoxymethyl-5-but-3-enyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-pyrazole

Ester hydrolysis was carried out as in Example 1, Part C.

From3-methoxymethyl-5-but-3-enyl-1-[(2'-carbomethoxybiphenyl-yl)methyl]pyrazole(815 mg, 2.09 mmol) was obtained 640 mg (81%) of the title compound as alight yellow solid; m.p. 100°-106° C.

NMR (200 MHz;CDCl₃,TMS) δ:7.94-7.05(m,8H), 6.13(s,1H), 5.80-5.60(m,1H),5.17(s,2H), 5.05-4.96(m,2H), 4.48(s,2H), 3.38(s,3H), 2.61(t,J=8 Hz,2H),2.31(m,2H).

EXAMPLE 173 Part A: 1-Methoxy-2,4-heptadione

This diketone was prepared using the same procedure in Example 170, PartA.

From 2-pentanone (8.6 g, 100 mmol), methyl methoxyacetate (21 g, 200mmol), and sodium methoxide (7.5 g, 110 mmol) in toluene (250 ml) wasobtained 6.3 g (40%) of the title compound following distillation at 4mm Hg; b.p. 98°-108° C.

NMR (200 MHz;CDCl₃,TMS) δ:5.79(s,1H), 3.99(s,2H), 3.43(s,3H), 2.30(t,J=7Hz,2H), 1.71-1.60(m,2H), 0.96(t,J=7 Hz,3H).

Part B: 3(5)-Methoxymethyl-5(3)-propylpyrazole

This compound was prepared using the same procedure in Example 170, PartB.

From 1-methoxy-2,4-heptadione (7.0 g, 44.2 mmol) and hydrazinemonohydrate (3.3 g, 66.4 mmol) was obtained 5.7 g (84%) of the titlecompound as a red liquid.

NMR (200 MHz;CDCl₃,TMS) δ:10.5-9.5(br,1H), 6.06(s,1H), 4.48(s,2H),3.37(s,3H), 2.60(t,J=7.5 Hz,2H), 1.70-1.59(m,2H), 0.94(t,J=7.5 Hz,3H).

Part C: 3-Methoxymethyl-5-propyl- and5-methoxymethyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazole

This compound was prepared using the procedure in Example 170, Part C.

From 3(5)-methoxymethyl-5(3)-propylpyrazole (3.4 g, 22 mmol), methyl4'-bromomethylbiphenyl-2-carboxylate (8.7 g, 28.5 mmol) and sodiumhydride (0.6 g, 26.4 mmol) in DMF (100 ml) was obtained, followingworkup and flash chromatography, 1.23 g (15%) of the 5-methoxymethyl(high R_(f)) isomer and 3.80 g (46%) of the 3-methoxymethyl (low R_(f))isomer.

NMR (high R_(f) ;200 MHz; CDCl₃,TMS) δ:7.82-7.06(m,8H), 6.14(s,1H),5.32(s,2H), 4.46(s,2H), 3.61(s,3H), 3.41(s,3H), 2.50(t,J=7 Hz,2H),1.67-1.56(m,2H), 0.94(t,J=7 Hz,3H).

NMR (low R_(f) ;200 MHz;CDCl₃,TMS) δ:7.82-7.12(m,8H), 6.08(s,1H),5.37(s,2H), 4.33(s,2H), 3.61(s,3H), 3.29(s,3H), 2.61(t,J=7 Hz,2H),1.73-1.66(m,2H), 0.97(t,J=7 Hz,3H).

Part D:3-Methoxymethyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

Hydrolysis of this pyrazole ester was carried out in the same fashion asin Example 1, Part C.

From3-methoxymethyl-5-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazole(807 mg, 2.13 mmol) was obtained 546 mg (70%) of the title compound as alight yellow solid; 48°-53° C.

NMR (200 MHz;CDCl₃,TMS) δ:7.94-7.05(m,8H), 6.11(s,1H), 5.16(s,2H),4.48(s,2H), 3.38(s,3H), 2.49(t,J=7.5 Hz,2H), 1.64-1.53(m,2H),0.93(t,J=7.5 Hz,3H).

EXAMPLE 1745-Methoxymethyl-3-propyl-1-[2'-carboxybiphenyl-4-yl)methyl]pyrazole

Hydrolysis was performed in the same fashion as in Example 1, Part C.

From5-methoxymethyl-3-propyl-1-[(2'-carbomethoxy-biphenyl-4-yl)methyl]pyrazole(701 mg, 1.85 mmol) was obtained 432 mg (64%) of the title compound as awhite solid; m.p. 100°-104° C.

NMR (200 MHz, CDCl₃,TMS) δ:7.93-7.10(m,8H), 6.03(s,1H), 5.14(m,2H),4.31(s,2H), 3.29(s,3H), 2.63(t,J=7.5 Hz,2H), 1.66-1.59(m,2H), 0.94(t,J=7Hz,3H).

EXAMPLE 175 Part A: Ethyl 2,4-dioxoheptanoate

To refluxing solution of sodium ethoxide (51.2 g, 0.75 mmol) in ethanol(170 ml) was added dropwise over 30 minutes a solution of 2-pentanone(59 g, 0.68 mol) in diethyl oxalate (99 g, 0.68 mol). The resultingturbid yellow mixture was refluxed further for 2 hours, cooled to roomtemperature, poured over 500 g ice with stirring and adjusted to pH 1-2with concentrated sulfuric acid (˜40 ml). The organic phase wasextracted with benzene (3×300 ml), washed once with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate, before beingfiltered, concentrated, and fractionally distilled at 0.1 mm Hg to give48.2 g (38%) of the title compound as a yellow liquid; b.p. 85°-95° C.

NMR (200 MHz; CDCl₃ , TMS): δ14.6-14.3 (br, 1H; --OH of enol), 6.37(s,1H; vinyl-H of enol), 4.35 (q,J=7 Hz,2H), 2.48 (t,J=7 Hz,2H),1.75-1.64 (m,2H), 1.38 (t,J=7 Hz,3H), 0.98 (t,J=7 Hz,3H).

Part B: Ethyl 3(5)-propylpyrazole-5(3)-carboxylate

This compound was prepared in an analogous fashion to Example 170, PartB. In this case, however, equimolar quantities of diketone and hydrazinehydrate were used and the reaction mixture was stirred at roomtemperature several hours (instead of at reflux, to avoid reaction ofthe ester function with hydrazine).

From ethyl 2,4-dioxoheptanoate (19.5 g, 0.11 mmol) and hydrazine hydrate(5.2 g, 0.11 mmol) in ethanol (450 ml) was obtained 20 g (100%) of thetitle compound as a yellow oil, used in subsequent reactions withoutfurther purification.

NMR (200 MHz;CDCl₃,TMS) δ:14.5-14.0(br,1H), 6.37(s,1H), 4.35(q,J=7Hz,2H), 2.48(t,J=7 Hz,2H), 1.75-1.64(m,2H), 1.38(t,J=7 Hz,3H),0.97(t,J=7 Hz,3H).

Part C: 3-Carboethoxy-5-propyl- and5-carboethoxy-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)-methyl]pyrazoles

These isomers were prepared using the procedure for Example 172, Part C.

From ethyl 3(5)-propylpyrazole-5(3)-carboxylate (3.0 g, 16.5 mmol),methyl 4'-bromomethylbiphenyl-2-carboxylate (5.5 g, 18.1 mmol) andpotassium carbonate (2.5 g, 18.1 mmol) in DMF (100 ml) was obtained,following workup and flash chromatography, 2.1 g (31%) of the5-carboethoxy (high R_(f)) isomer and 2.7 g (40%) of the 3-carboethoxyisomer.

NMR (low R_(f) ; 200 MHz;CDCl₃,TMS) δ:7.84-7.09(m,8H), 6.67(s,1H),5.44(s,2H), 4.42(q,J=7 Hz,2H), 3.62(s,3H), 2.50(t,J=7 Hz,2H),1.68-1.56(m,2H), 1.41(t,J=7 Hz,3H), 0.97(t,J=7 Hz,3H).

NMR (high R_(f) ; 200 MHz; CDCl₃,TMS) δ:7.82-7.23 (m,8H), 6.70(s,1H),5.76(s,2H), 4.29(q,J=7 Hz,2H), 3.60(s,3H), 2.64(t,J=7 Hz,2H),1.75-1.64(m,2H), 1.33(t,J=7 Hz,3H), 0.97(t,J=7 Hz,3H).

Part D: 3-Carboxy-5-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

Hydrolysis of these pyrazole diesters was carried out in the samefashion as in Part C, Example 1.

From3-carboethoxy-5-propyl-1-[(2'-carbomethoxy-biphenyl-4-yl)methyl]pyrazole(1.4 g, 3.4 mmol) was obtained 0.92 g (73%) of the corresponding titlecompound as a light yellow solid; m.p. 218°-222° C.

NMR (200 MHz;CDCl₃,TMS) δ:7.90-7.08(m,8H), 6.66(s,1H), 5.39(s,2H),3.67(br,4H; CO₂ H+H₂ O), 2.54(t,J=7.5 Hz,2H), 1.69-1.58(m,2H),0.95(t,J=7 Hz,3H).

EXAMPLE 176 Part A: 3(5)-Hydroxymethyl-5(3)-propylpyrazole

To a slurry of lithium aluminum hydride (5.0 g, 132 mmol) in anhydrousether (250 ml) was added dropwise a solution of ethyl3(5)-propylpyrazole-5(3)-carboxylate (12.0 g, 65.8 mmol) in ether (250ml). The resulting mixture was refluxed for 2 hours, the excessreductant was quenched by the (careful) dropwise addition of ethylacetate, and the organic phase was washed with water before being driedover MgSO₄, filtered and concentrated to afford 8.7 g (95%) of the titlecompound as a pale yellow waxy solid.

NMR (200 MHz; CDCl₃,TMS) δ:5.99(s,1H), 4.64(s,2H), 2.56(t,J=7.5 Hz,2H),1.68-1.57(m,2H), 0.93(t,J=7 Hz,3H).

Part B: 3-Hydroxymethyl-5-propyl- and5-hydroxymethyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazoles

These isomers were prepared using the procedure of Example 172, Part C.

From 3(5)-hydroxymethyl-5(3)-propylpyrazole (4.0 g, 28.5 mmol) wasobtained 10.6 g of the crude title compounds which were separated byflash chromatography on silica gel (50% EtOAc/hexanes, then EtOAc).

Isolated was 3.79 g (37%) of the 5-hydroxymethyl-3-propyl isomer (highR_(f)): NMR (200 MHz; CDCl₃,TMS) δ:7.83-7.12(m,8H), 6.06(s,1H),5.38(s,2H), 4.54(s,2H), 3.61(s,3H), 2.59(t,J=8 Hz,2H), 1.72-1.61(m,2H),0.97(t,J=7 Hz,3H).

Also isolated was 1.70 g (17%) of the 3-hydroxymethyl-5-propyl isomer(low R_(f)): NMR (200 MHz; CDCl₃,TMS) δ:7.84-7.07(m,8H), 6.11(s,1H),5.31(s,2H), 4.68(s,2H), 3.63(s,3H), 2.51(t,J=7.5 Hz,2H),1.68-1.57(m,2H), 0.96(t,J=7 Hz,3H).

Part C:3-Hydroxymethyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

This compound was prepared according to the procedure of Example 1, PartC.

From3-hydroxymethyl-5-propyl-1-[(2'-carbomethoxy-biphenyl-4-yl)methyl]pyrazole(1.5 g, 4.1 mmol) was obtained 1.4 g (99%) of the title compound as anoff-white solid, m.p. 119°-125° C.

NMR (200 MHz; CDCl₃,TMS) δ:7.48-7.00(m,8H), 6.03(s,1H), 4.85(s,2H),4.62(s,2H), 2.47(t,J=8 HZ,2H), 1.59-1.49(m,2H), 0.93(t,J=7 Hz,3H).

EXAMPLE 1775-Hydroxymethyl-3-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

This compound was prepared according to the procedure of Example 1, PartC.

From5-hydroxymethyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazole(2.0 g, 5.5 mmol) was obtained 1.7 g (89%) of the title compound as anoff-white solid, m.p. 51°-58° C.

NMR (200 MHz; CDCl₃,TMS) δ:7.91-7.04(m,8H), 5.99(s,1H), 5.16(s,2H),4.43(s,2H), 2.55(t,J=7.5 Hz,2H), 1.66-1.55(m,2H), 0.92(t,J=7 Hz,3H).

EXAMPLE 178 Part A: 3(5)-Formyl-5(3)-propylpyrazole

To a solution of 3(5)-hydroxymethyl-5(3)-propyl-pyrazole (6.6 g, 47.1mmol) in methylene chloride (250 ml) was added activated manganesedioxide (41 g, 471 mmol). The mixture was stirred overnight at roomtemperature before being filtered and concentrated to afford 5.8 g (89%)of the title compound as a pale yellow solid.

NMR (200 MHz; DMSO-d₆,TMS) δ:9.84(s,1H), 6.53(2s,1H), 2.61(t,J=7.5Hz,2H), 1.68-1.53(m,2H), 0.89(t,J=8 Hz,3H).

Part B: 3-Formyl-5-propyl- and5-formyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazoles

These isomers were prepared using the procedure for Example 172, Part C.

From 3(5)-formyl-5(3)-propylpyrazole (2,5 g, 18.1 mmol) was obtained 7.3g of the crude title compounds which were separated by flashchromatography on silica gel (15% EtOAc/hexanes).

Isolated was 1.31 (20%) of the 5-formyl-3-propyl-isomer (high R_(f)):NMR (200 MHz; CDCl₃,TMS) δ:9.79(s,1H), 7.82-7.20(m,8H), 6.73(s,1H),5.71(s,2H), 3.59(s,3H), 2.66(t,J=7.5 Hz,2H), 1.75-1.65(m,2H), 0.98(t,J=7Hz,3H).

Also isolated was 2.94 g (45%) of the 3-formyl-5-propyl-isomer (lowR_(f)): NMR (200 MHz; CDCl₃,TMS) δ:9.97(s,1H), 7.86-7.12(m,8H),6.65(s,1H), 5.43(s,2H), 3.64(s,3H), 2.55(t,J=7.5 Hz,2H),1.70-1.59(m,2H), 0.96(t,J=7 Hz,3H).

Part C: 3-Formyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

This compound was prepared according to the procedure illustrated byExample 1, Part C.

From 3-formyl-5-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazole(1.5 g, 4.1 mmol) was obtained 420 mg (29%) of the title compound as anamorphous solid following flash chromatography on silica gel (EtOAc).

NMR (200 MHz; CDCl₃,TMS) δ:9.94(s,1H), 7.96-7.10(m,8H), 6.64(s,1H),5.41(s,2H), 2.53(t,J=7.5 Hz,2H), 1.67-1.56(m,2H), 0.93(t,J=7 Hz,3H).

EXAMPLE 179 Part A:5-Formyl-3-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrazole

This compound was prepared according to the procedure of Example 1, PartC.

From 5-formyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]pyrazole(0.94 g, 2.6 mmol) was obtained 600 mg (66%) of the title compound as ayellow solid following flash chromatography on silica gel (EtOAc), m.p.149°-153° C.

NMR (200 MHz; CDCl₃,CD₃ OD,TMS) δ:9.80(m,1H), 7.89-7.13(m,8H),6.77(s,1H), 5.69(s,2H), 2.66(t,J=7.5 Hz,2H), 1.76-1.61(m,2H), 0.98(t,J=7Hz,3H).

Table 3 lists examples of pyrazoles of this invention which wereprepared or could be prepared by procedures of Examples 170-179 or byprocedures previously described herein.

                                      TABLE 3                                     __________________________________________________________________________    PYRAZOLES                                                                      ##STR47##                                                                    Ex.                                                                           No.                                                                              R.sup.1    R.sup.2      R.sup.3                                                                             R.sup.5                                                                           A     m.p. (°C.)                  __________________________________________________________________________    170                                                                              CH.sub.2 OCH.sub.3                                                                        -n-butyl    CO.sub.2 H                                                                          H   Single bond                                                                         129-134                            171                                                                               -n-butyl  CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                                                                         112-119                            172                                                                              (CH.sub.2).sub.2 CHCH.sub.2                                                              CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                                                                         100-106                            173                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                                                                          48-53                             174                                                                              CH.sub.2 OCH.sub.3                                                                        -n-propyl   CO.sub.2 H                                                                          H   Single bond                                                                         100-104                            175                                                                               -n-propyl CO.sub.2 H   CO.sub.2 H                                                                          H   Single bond                                                                         218-222 (dec.)                     176                                                                                -n-propyl                                                                              CH.sub.2 OH  CO.sub.2 H                                                                          H   Single bond                                                                         119-125                            177                                                                              CH.sub.2 OH                                                                               -n-propyl   CO.sub.2 H                                                                          H   Single bond                                                                          51-58                             178                                                                               -n-propyl CHO          CO.sub.2 H                                                                          H   Single bond                                                                         (amorph)                           179                                                                              CHO         -n-propyl   CO.sub.2 H                                                                          H   Single bond                                                                         149-153                            180                                                                              CH.sub.2 OCH.sub.3                                                                       Et           CO.sub.2 H                                                                          H   Single bond                              181                                                                               -n-C.sub.5 H.sub.11                                                                     CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                              182                                                                              CH.sub.2 OCH.sub.3                                                                        -n-C.sub.6 H.sub.13                                                                       CO.sub.2 H                                                                          H   Single bond                              183                                                                              CHCHCH.sub.3                                                                             CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                              184                                                                              CH.sub.2 OCH.sub.3                                                                       CHCH(CH.sub.2).sub.2 CH.sub.3                                                              CO.sub.2 H                                                                          H   Single bond                              185                                                                              CHCH(CH.sub.2).sub.3 CH.sub.3                                                            CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                              186                                                                              CH.sub.2 OCH.sub.3                                                                       CCCH.sub.3   CO.sub.2 H                                                                          H   Single bond                              187                                                                              CCCH.sub.2 CH.sub.3                                                                      CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                              188                                                                              CH.sub.2 OCH.sub.3                                                                       CC(CH.sub.2).sub.2 CH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                              189                                                                              CC(CH.sub.2).sub.3 CH.sub.3                                                              CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                              190                                                                              (CH.sub.2).sub.2 OCH.sub.3                                                                -n-propyl   CO.sub.2 H                                                                          H   Single bond                              191                                                                               -n-propyl (CH.sub.2).sub.3 OCH.sub.3                                                                 CO.sub.2 H                                                                          H   Single bond                              192                                                                              (CH.sub.2).sub.4 OCH.sub.3                                                                -n-propyl   CO.sub.2 H                                                                          H   Single bond                              193                                                                               -n-propyl (CH.sub.2).sub.5 OCH.sub.3                                                                 CO.sub.2 H                                                                          H   Single bond                              194                                                                              (CH.sub.2).sub.6 OCH.sub.3                                                                -n-propyl   CO.sub.2 H                                                                          H   Single bond                              195                                                                               -n-propyl CH.sub.2 OCH.sub.2 CH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                              196                                                                              CH.sub.2 O(CH.sub.2).sub.2 CH.sub.3                                                       -n-propyl   CO.sub.2 H                                                                          H   Single bond                              197                                                                               -n-propyl CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                        CO.sub.2 H                                                                          H   Single bond                              198                                                                               -n-propyl CO.sub.2 CH.sub.3                                                                          CO.sub.2 H                                                                          H   Single bond                              199                                                                               -n-propyl CO.sub.2 C.sub.2 H.sub.5                                                                   CO.sub.2 H                                                                          H   Single bond                              200                                                                               -n-propyl CO.sub.2 - -n-C.sub.3 H.sub.7                                                              CO.sub.2 H                                                                          H   Single bond                              201                                                                               -n-propyl CO.sub.2 - -n-C.sub.4 H.sub.9                                                              CO.sub.2 H                                                                          H   Single bond                              202                                                                               -n-propyl CO.sub.2 - -n-C.sub.5 H.sub.11                                                             CO.sub.2 H                                                                          H   Single bond                              203                                                                               -n-propyl CO.sub.2 - -c-C.sub.3 H.sub.5                                                              CO.sub.2 H                                                                          H   Single bond                              204                                                                               -n-propyl CO.sub.2 - -c-C.sub.4 H.sub.7                                                              CO.sub.2 H                                                                          H   Single bond                              205                                                                               -n-propyl CO.sub.2 - -c-C.sub.5 H.sub.9                                                              CO.sub.2 H                                                                          H   Single bond                              206                                                                               -n-propyl CO.sub.2 - -c-C.sub.6 H.sub.11                                                             CO.sub.2 H                                                                          H   Single bond                              207                                                                               -n-propyl CO.sub.2 Ph  CN.sub.4 H                                                                          H   Single bond                              208                                                                               -n-propyl CO.sub.2 CH.sub.2 Ph                                                                       CN.sub.4 H                                                                          H   Single bond                              209                                                                               -n-propyl CH.sub.2 COPh                                                                              CO.sub.2 H                                                                          H   Single bond                              210                                                                               -n-propyl CH.sub.2 COCH.sub.2 Ph                                                                     CO.sub.2 H                                                                          H   Single bond                              211                                                                               -n-propyl CH.sub.2 CO(CH.sub.2).sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                              212                                                                               -n-propyl CH.sub.2 CO(CH.sub.2).sub.3 Ph                                                             CO.sub.2 H                                                                          H   Single bond                              213                                                                               -n-propyl (CH.sub.2).sub.4 COCH.sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                              214                                                                               -n-propyl (CH.sub.2).sub.5 COCH.sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                              215                                                                               -n-propyl (CH.sub.2).sub.6 COCH.sub.2 Ph                                                             CO.sub.2 H                                                                          H   Single bond                              216                                                                               -n-propyl CONH.sub.2   CO.sub.2 H                                                                          H   Single bond                              217                                                                               -n-propyl CONHCH.sub.3 CO.sub.2 H                                                                          H   Single bond                              218                                                                               -n-propyl CON(CH.sub.3).sub.2                                                                        CO.sub.2 H                                                                          H   Single bond                              219                                                                               -n-propyl CONHEt       CO.sub.2 H                                                                          H   Single bond                              220                                                                               -n-propyl CONH- -n-Pr  CO.sub.2 H                                                                          H   Single bond                              221                                                                               -n-propyl CONH- -n-Bu  CO.sub.2 H                                                                          H   Single bond                              222                                                                               -n-propyl CONHPh       CO.sub.2 H                                                                          H   Single bond                              223                                                                               -n-propyl CONHCH.sub.2 Ph                                                                            CO.sub.2 H                                                                          H   Single bond                              224                                                                               -n-propyl                                                                                ##STR48##   CO.sub.2 H                                                                          H   Single bond                              225                                                                               -n-propyl                                                                                ##STR49##   CO.sub.2 H                                                                          H   Single bond                              226                                                                               -n-propyl                                                                                ##STR50##   CO.sub.2 H                                                                          H   Single bond                              227                                                                               -n-propyl                                                                                ##STR51##   CO.sub.2 H                                                                          H   Single bond                              228                                                                               -n-propyl                                                                                ##STR52##   CO.sub.2 H                                                                          H   Single bond                              229                                                                               -n-propyl                                                                                ##STR53##   CO.sub.2 H                                                                          H   Single bond                              230                                                                               -n-propyl                                                                                ##STR54##   CO.sub.2 H                                                                          H   Single bond                              231                                                                               -n-propyl                                                                                ##STR55##   CO.sub.2 H                                                                          H   Single bond                              232                                                                               -n-propyl                                                                                ##STR56##   CN.sub.4 H                                                                          H   Single bond                              233                                                                               -n-propyl CH.sub.2 SCH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                              234                                                                               -n-propyl                                                                                ##STR57##   CO.sub.2 H                                                                          H   Single bond                              235                                                                               -n-propyl CH.sub.2 SO.sub.2 CH.sub.3                                                                 CO.sub.2 H                                                                          H   Single bond                              236                                                                               -n-propyl CHCHCH.sub.2 OH                                                                            CO.sub.2 H                                                                          H   Single bond                              237                                                                               -n-propyl CHCHCH.sub.2 OCH.sub.3                                                                     CO.sub.2 H                                                                          H   Single bond                              238                                                                                -n-propyl                                                                              CHCHCH.sub.2 OEt                                                                           CO.sub.2 H                                                                          H   Single bond                              239                                                                               -n-propyl CHCHCH.sub.2 O- -n-C.sub.3 H.sub.7                                                         CO.sub.2 H                                                                          H   Single bond                              240                                                                               -n-propyl CHCHCH.sub.2 O- -n-C.sub.4 H.sub.9                                                         CO.sub.2 H                                                                          H   Single bond                              241                                                                               -n-propyl                                                                                ##STR58##   CO.sub.2 H                                                                          H   Single bond                              242                                                                               -n-propyl                                                                                ##STR59##   CO.sub.2 H                                                                          H   Single bond                              243                                                                               -n-propyl                                                                                ##STR60##   CO.sub.2 H                                                                          H   Single bond                              244                                                                               -n-propyl                                                                                ##STR61##   CO.sub.2 H                                                                          H   Single bond                              245                                                                               -n-propyl                                                                                ##STR62##   CO.sub.2 H                                                                          H   Single bond                              246                                                                               -n-propyl                                                                                ##STR63##   CO.sub.2 H                                                                          H   Single bond                              247                                                                               -n-propyl CH.sub.2 NHCO.sub.2 CH.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                              248                                                                               -n-propyl CH.sub.2 NHCO.sub.2 Et                                                                     CO.sub.2 H                                                                          H   Single bond                              249                                                                               -n-propyl CH.sub.2 NHCO.sub.2 - -n-C.sub.3 H.sub.7                                                   CO.sub.2 H                                                                          H   Single bond                              250                                                                               -n-propyl CH.sub.2 NHCO.sub.2 - -n-C.sub.4 H.sub.9                                                   CO.sub.2 H                                                                          H   Single bond                              251                                                                               -n-propyl CH.sub.2 NHCO.sub.2 - -n-C.sub.5 H.sub.11                                                  CO.sub.2 H                                                                          H   Single bond                              252                                                                               -n-propyl CH.sub.2 NHCO.sub.2 - -n-C.sub.6 H.sub.13                                                  CO.sub.2 H                                                                          H   Single bond                              253                                                                               -n-propyl CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                              254                                                                               -n-propyl CH.sub.2 NHCO.sub.2 CF.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                              255                                                                               -n-propyl CH.sub.2 NHSO.sub.2 CH.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                              256                                                                               - n-propyl                                                                              CH.sub.2 NHSO.sub.2 C.sub.2 F.sub.5                                                        CO.sub.2 H                                                                          H   Single bond                              257                                                                               -n-propyl CH.sub.2 NHSO.sub.2 - -n-C.sub.3 F.sub.7                                                   CO.sub.2 H                                                                          H   Single bond                              258                                                                               -n-propyl CH.sub.2 NHSO.sub.2 - -n-C.sub.4 F.sub.9                                                   CO.sub.2 H                                                                          H   Single bond                              259                                                                               -n-propyl CH.sub.2 NHSO.sub.2 - -n-C.sub.5 F.sub.11                                                  CO.sub.2 H                                                                          H   Single bond                              260                                                                               -n-propyl CH.sub.2 NHSO.sub.2 - -n-C.sub.6 F.sub.13                                                  CO.sub.2 H                                                                          H   Single bond                              261                                                                               -n-propyl CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                              262                                                                               -n-propyl CH.sub.2 F   CO.sub.2 H                                                                          H   Single bond                              263                                                                               -n-propyl CH.sub.2 CN.sub.4 H                                                                        CO.sub.2 H                                                                          H   Single bond                              264                                                                               -n-propyl CH.sub.2 NHCO.sub.2 Ph                                                                     CO.sub.2 H                                                                          H   Single bond                              265                                                                               -n-propyl CH.sub.2 NHCO.sub.2 (CH.sub.2).sub.2 Ph                                                    CO.sub.2 H                                                                          H   Single bond                              266                                                                               -n-propyl CH.sub.2 NHCO.sub.2 (CH.sub.2).sub.3 Ph                                                    CO.sub.2 H                                                                          H   Single bond                              267                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          NO.sub.2                                                                          NHCO                                     268                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          OCH.sub.3                                                                         NHCO                                     269                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          CH.sub.3                                                                          NHCO                                     270                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          F   NHCO                                     271                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          Cl  NHCO                                     272                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         CO.sub.2 H                                                                          Br  NHCO                                     273                                                                               -n-propyl CH.sub.2 OCH.sub.3                                                                         NHSO.sub.2 CF.sub.3                                                                 I   NHCO                                     274                                                                               -n-propyl CH.sub.2 OH  CO.sub.2 H                                                                          H   CO                                       275                                                                               -n-propyl CH.sub.2 OH  CO.sub.2 H                                                                          H   O                                        276                                                                               -n-propyl CO.sub.2 H   CO.sub.2 H                                                                          H   OCH.sub.2                                __________________________________________________________________________

EXAMPLE 277 Part A: Ethyl5-formyl-1-[2'(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure for Example 172,Part C.

From ethyl 5-formylpyrrole-2-carboxylate (10.0 g, 57.8 mmol) and4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl (37.0 g, 65.8mmol) was obtained 18.4 g (48%) of the title compound as a light pinksolid; m.p. 64°-72° (dec.).

NMR (200 MHz; CDCl₃,TMS) δ:9.6(s,1H), 7.9-6.8(m,25H), 6.05(s,2H),4.2(q,J=7 Hz,2H), 1.25(t,J=7 Hz,3H).

Part B: Ethyl5-(1-hydroxypropyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

Into a solution of5-formyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(2.0 g, 3.1 mmol) in dry ether (100 ml) cooled to -78° C. was syringed asolution of ethyl magnesium bromide (1.3 ml of a 3.0M solution in ether;4.0 mmol) dropwise over 10 minutes. The mixture was allowed to stir for2 hours while being allowed to warm to room temperature. The mixture wasquenched with 10% aqueous ammonium chloride (20 ml) and the organicphase was washed with saturated aqueous sodium bicarbonate (50 ml),saturated aqueous sodium chloride (50 ml) and dried (MgSO₄) before beingfiltered and concentrated to leave 2.0 g (95%) of a white solid whichcould be chromatographed on silica gel but was generally used withoutfurther purification, being one spot by tlc.

NMR (200 MHz; CDCl₃,TMS) δ:7.87-6.72(m,24H), 6.22(d,J=4 Hz,1H),5.72(ABq,J=12 Hz,J=16 Hz,2H), 4.42-4.28(m,1H), 4.16(q,J=7 Hz,2H),1.81-1.74(m,2H), 1.26(t,J=7 Hz,3H), 0.82(t,J=7 Hz,3H).

Part C: (Cis- and trans-)ethyl5-(1-propenyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

To a solution of ethyl5-(1-hydroxypropyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(2.0 g, 3.0 mmol) in methylene chloride (100 ml) at 0° C. was added DBU(2.0 ml, 12.0 mmol) followed by methanesulfonyl chloride (0.7 ml, 9.0mmol). The mixture was stirred overnight at room temperature whereuponan additional aliquot of DBU (2.0 ml) and methanesulfonyl chloride (0.7ml) were added and the mixture was allowed to stir an additional 24hours. The mixture was poured into a separatory funnel and washed withwater (3×50 ml) and saturated aqueous sodium bicarbonate solution (50ml) before being dried (MgSO₄), filtered and concentrated. The cruderesidue was purified by flash chromatography on silica gel (150 g,10-30% EtOAc/hexanes) to give the title compounds as a mixture ofcis/trans isomers (ca. 1/4).

NMR (200 MHz; CDCl₃,TMS; trans-isomer) δ:7.88-6.75(m,24H), 6.33(d,J=4Hz,1H), 6.19-6.13(m,2H), 5.56(s,2H), 4.14(q,J=7 Hz,2H), 1.68(d,J=5Hz,3H), 1.24(t,J=7 Hz,3H).

The cis-isomer was evident by virtue of a weak benzylic methylene(singlet) at 5.66 δ as well as a comparably weak allylic methyl(doublet, J=5 Hz) at 1.85 δ.

This cis-trans mixture could be carried through to the next step orlater separated following subsequent transformations, leading topropenyl analogues.

Part D: Ethyl5-n-propyl-1-[2'-(1-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

A solution of (cis- and trans-) ethyl5-(1-propenyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(350 mg, 0.53 mmol) in benzene (35 ml) containing 5% Pd/C (35 mg) in aPaar bottle was placed on a Paar apparatus under 40 psi H₂ and shakenfor about 4 hours at room temperature. The mixture was suction filteredthrough Celite and concentrated to leave 350 mg of a white solid.

NMR (200 MHz; CDCl₃,TMS) δ:7.88-6.68(m,24H), 6.01(d,J=4 Hz,1H),5.53(s,2H), 4.14(q,J=7 Hz,2H), 2.33(t,J=7.5 Hz,2H), 1.57-1.50(m,2H),1.25(t,J=7 Hz,3H), 0.83(t,J=7.5 Hz,3H).

Part E: Ethyl5-n-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure of Example 3, PartC.

From ethyl5-n-propyl-1-[2'-(1-triphenyl-methyltetrazol-5-yl)biphenyl-4-yl-methyl]-pyrrole-2-carboxylate(400 mg, 0.6 mmol) was obtained 126 mg (50%) of the title compound as anamorphous white solid.

NMR (200 MHz; CDCl₃,TMS) δ:7.87-6.83(m,9H), 6.05(d,J=4 Hz,1H),5.56(s,2H), 4.20(q,J=7 Hz,2H), 2.48(t,J=7.5 Hz,2H), 1.68-1.57(m,2H),1.31(t,J=7 Hz,3H), 0.95(t,J=7 Hz,3H).

EXAMPLE 278 Part A: Ethyl5-formyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure of Example 172,Part C.

From ethyl 5-formylpyrrole-2-carboxylate (4.0 g, 23.9 mmol) and t-butyl4'-bromomethylbiphenyl-2-carboxylate (10.0 g, 28.7 mmol) was obtained8.2 g (71%) of the title compound as a pale yellow oil following flashchromatography on silica gel (10% EtOAc/hexanes).

NMR (200 MHz; CDCl₃,TMS) δ:9.75(s,1H), 7.78-6.96 (m,10H), 6.19(s,2H),4.30(q,J=d7.5 Hz,2H), 1.35(t,J=7.5 Hz, 3H), 1.15(s,9H).

Part B: Ethyl5-(1-hydroxypropyl)-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure of Example 277,Part B.

From ethyl5-formyl-1-[(2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]pyrrole-2-carboxylate(7.2 g, 16.6 mmol) was obtained 6.4 g (83%) of the title compoundfollowing flash chromatography on silica gel (10% EtOAc/hexanes).

NMR (200 MHz; CDCl₃, TMS) δ: 7.77-6.90 (m, 9 H), 6.24(d, J=4 Hz, 1 H),5.85 (ABq, J=17 Hz, J=23 Hz,2 H), 4.51 (m, 1 H), 4.20(q,J=7.5 Hz,2H),1.89(m,2H), 1.27(t,J=7.5 Hz,3H), 1.21(s,9H), 0.95(t,J=7.5 Hz,3H).

Part C: (Cis- and trans-) ethyl5-(1-propenyl)-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate

This cis/trans mixture (only about 10% of the cis-isomer was observed inthis case) was prepared according to the procedure of Example 277, PartC.

From ethyl5-(1-hydroxypropyl)-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate(5.7 g, 12.3 mmol) was obtained the title compounds as a yellow viscousoil following flash chromatography on silica gel.

NMR (200 MHz; CDCl₃, TMS, trans-isomer) δ: 7.77-6.99(m,10H),6.35-6.25(m,2H), 5.72(s,2H), 4.22(q,J=7 Hz,2H), 1.83(d,J=5 Hz, 3H), 1.26(t,J=7 Hz,3H), 1.18(s,9H).

Part D: Ethyl5-n-propyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure of Example 277,Part D.

From (cis- and trans-) ethyl5-(1-propenyl)-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate(1.2 g, 2.7 mmol) was obtained 0.9 g (75%) of the title compound as aviscous oil following flash chromatography on silica gel (10%EtOAc/hexanes).

NMR (200 MHz; CDCl₃, TMS) δ: 7.78-6.90(m,9H), 6.05(d, J=4 Hz,1H),5.68(s,2H), 4.20(q,J=7 Hz,2H), 2.51(t,J=7.5 Hz, 2H), 1.72-1.57(m,2H),1.29(t,J=7 Hz,3H), 1.20(s,9H), 0.96(t,J=7 Hz,3H).

Part E: Ethyl5-n-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrrole-2-carboxylate

Ethyl5-n-propyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate(600 mg, 1.34 mmol) was stirred with formic acid (6 ml) at roomtemperature for 4 hours (slowly dissolved to a homogenous yellowsolution). The mixture was diluted to about 50 ml with water to give awhite precipitate which was filtered and subsequently purified by flashchromatography on silica gel (10% EtOAc/hexanes) to give 419 mg (80%) ofthe compound: m.p. 111°-115° C.

NMR (200 MHz; CDCl₃, TMS) δ: 7.92-6.91(m,9H), 6.02(d, J=4 Hz,1H),5.65(s,2H), 4.19(q,J=7 Hz,2H), 2.49(t,J=7.5 Hz, 2H), 1.67-1.55(m,2H),1.26(t,J=7 Hz,3H), 0.92(t,J=7 Hz,3H).

EXAMPLE 279 Part A:5-n-Propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-pyrrole-2-carboxylic acid

This compound was prepared using the procedure of Example 1, Part C.

From ethyl5-n-propyl-1-[(2'-carboxybiphenyl-4-yl)methyl]pyrrole-2-carboxylate (235mg, 0.6 mmol) was obtained 188 mg (86%) of the title compound as a whitesolid; m.p. 135°-137° C. (dec.).

NMR (200 MHz; CDCl₃, CD₃ OD,TMS) δ: 7.86-6.88(m,9H), 6.05(d,J=4 Hz,1H),5.62(s,2H), 2.50(t,J=7 Hz,2H), 1.70-1.58(m,2H), 0.95(t,J=7 Hz,3H).

EXAMPLE 280 Part A: 5-n-propylpyrrole-2-carboxaldehyde

To an anhydrous solution of 6-dimethylamino-1-azafulvene dimer (125;12.0 g, 49.1 mmol) in THF (500 ml) at -15° C. was added dropwise asolution of 5-butyllithium in pentane (1.7M; 87 ml, 147 mmol) over 5minutes. The yellow cloudy solution was slowly warmed to 0° C. over 10minutes and stirred at this temperature for a further 20 minutes. Theresulting deep violet colored solution was treated with 1-iodopropane(19.2 ml, 196 mmol) and allowed to warm to room temperature over 2hours. The mixture was treated with water (20 ml) and saturated aqueoussodium bicarbonate (20 ml) and refluxed for 15 hours. The mixture wasextracted into methylene chloride and the organic phase was washed withsaturated aqueous sodium bicarbonate, dried over anhydrous magnesiumsulfate, filtered and concentrated to a dark liquid residue (15.2 g) byrotary evaporation. Flash chromatography (silica gel, 500 g;EtOAc/hexanes, 5/95) gave 7.85 g (60%) of the title compound as a palebrown liquid.

NMR (200 MHz; CDCl₃, TMS) δ: 10.6-10.4 (br, 1H), 9.35 (s, 1H), 6.90 (t,J=1-2 Hz, 1H), 6.05 (t, J=1-2 Hz, 1H), 2.6 (t, J=7 Hz, 2H), 1.75-1.55(m, 2H), 1.0-0.8 (t, J=7 Hz, 3H).

PART B:5-n-propyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxaldehyde

To a solution of 5-n-propylpyrrole-2-carboxaldehyde (2.5 g, 18.9 mmol)and t-butyl 4'-bromomethylbiphenyl-2-carboxylate (7.2 g, 20.7 mmol) inmethylene chloride (75 ml) was added 2.5N NaOH (15 ml) and Aliquat 336(1.5 g, 3.7 mmol). The mixture was vigorously stirred at roomtemperature overnight (˜18 hours). The organic phase was washed withwater (50 ml) and saturated aqueous sodium chloride (50 ml) before beingdried (MgSO₄), filtered and concentrated to leave 10.1 g of a dark oilyresidue. Flash chromatography (silica gel, 300 g; EtOAc/hexanes, 1/9)gave 5.84 g (79%) of a pale yellow viscous oil.

NMR (200 MHz; CDCl₃, TMS) δ: 9.46 (s, 1H), 7.78-6.96 (m, 9H), 6.15 (d,J=3 Hz, 1H), 5.69 (s, 2H), 2.53 (t, J=7.5 Hz, 2H), 1.72-1.61 (m, 2H),1.20 (s, 9H), 0.97 (t, J=7 Hz, 3H).

PART C:5-n-propyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]pyrrole-2-carboxaldehyde

This compound was prepared according to the procedure for Example 278,Part E. In this case, dilution of the reaction mixture with water gavean oily precipitate; therefore, it was extracted into EtOAc and theorganic phase was dried (MgSO₄), filtered and concentrated before beingpurified by flash chromatography.

From5-n-propyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxaldehyde(1.0 g, 2.55 mmol) and formic acid (10 ml) was obtained 0.64 g (72%) ofthe title compound as an off-white solid; m.p. 117°-120° C.

NMR (200 MHz; CDCl₃, TMS) δ: 9.44 (s, 1H), 7.93-6.95 (m, 9H), 6.13 (d,J=4 Hz, 1H), 5.68 (s, 2H), 5.3-5.0 (br, 1H, washes out in D20), 2.51 (t,J=7.5 Hz, 2H), 1.67-1.55 (m, 2H), 0.92 (t, J=7 Hz, 3H).

Table 4 lists examples of pyrroles of this invention which were preparedor could be prepared by procedures of Examples 277-280 or by procedurespreviously described herein.

                                      TABLE 4                                     __________________________________________________________________________    PYRROLES                                                                       ##STR64##                                                                    Ex.                                                                           No.                                                                              R.sup.1    R.sup.2     R.sub.3                                                                             R.sup.5                                                                           A     m.p. (°C.)                   __________________________________________________________________________    277                                                                               -n-propyl CO.sub.2 Et CN.sub.4 H                                                                          H   Single bond                                                                         (amorph)                            278                                                                               -n-propyl CO.sub.2 Et CO.sub.2 H                                                                          H   Single bond                                                                         111-115                             279                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          H   Single bond                                                                         135-137                             280                                                                               -n-propyl CHO         CO.sub.2 H                                                                          H   Single bond                                                                         117-120                             281                                                                               -n-butyl  CHO         CN.sub.4 H                                                                          H   Single bond                               282                                                                              ethyl      CO.sub.2 CH.sub.3                                                                         CO.sub.2 H                                                                          H   Single bond                               283                                                                               -n-C.sub.5 H.sub.11                                                                     CO.sub.2 - -n-C.sub.3 H.sub.7                                                             CO.sub.2 H                                                                          H   Single bond                               284                                                                               - n-C.sub.6 H.sub.13                                                                    CO.sub.2 - -n-C.sub.4 H.sub.9                                                             CO.sub.2 H                                                                          H   Single bond                               285                                                                               -n-propyl CO.sub.2 - -n-C.sub.5 H.sub.11                                                            CO.sub.2 H                                                                          H   Single bond                               286                                                                               -n-propyl CO.sub.2 - -c-C.sub.3 H.sub.5                                                             CO.sub.2 H                                                                          H   Single bond                               287                                                                               -n-propyl CO.sub.2 - -c-C.sub.4 H.sub.7                                                             CO.sub.2 H                                                                          H   Single bond                               288                                                                               -n-propyl CO.sub.2 - -c-C.sub.5 H.sub.9                                                             CO.sub.2 H                                                                          H   Single bond                               289                                                                               -n-propyl CO.sub.2 - -c-C.sub.6 H.sub.11                                                            CO.sub.2 H                                                                          H   Single bond                               290                                                                               -n-propyl CO.sub.2 Ph CO.sub.2 H                                                                          H   Single bond                               291                                                                               -n-propyl CO.sub.2 CH.sub.2 Ph                                                                      CO.sub.2 H                                                                          H   Single bond                               292                                                                               -n-propyl CONH.sub.2  CO.sub.2 H                                                                          H   Single bond                               293                                                                               -n-propyl CONHCH.sub.3                                                                              CO.sub.2 H                                                                          H   Single bond                               294                                                                               -n-propyl CON(CH.sub.3).sub.2                                                                       CO.sub.2 H                                                                          H   Single bond                               295                                                                               -n-propyl CONHEt      CO.sub.2 H                                                                          H   Single bond                               296                                                                               -n-propyl CONH- -n-Pr CO.sub.2 H                                                                          H   Single bond                               297                                                                               -n-propyl CONH- -n-Bu CO.sub.2 H                                                                          H   Single bond                               298                                                                               -n-propyl CONHPh      CO.sub.2 H                                                                          H   Single bond                               299                                                                               -n-propyl CONHCH.sub.2 Ph                                                                           CO.sub.2 H                                                                          H   Single bond                               300                                                                               -n-propyl                                                                                ##STR65##  CO.sub.2 H                                                                          H   Single bond                               301                                                                               -n-propyl                                                                                ##STR66##  CO.sub.2 H                                                                          H   Single bond                               302                                                                               -n-propyl                                                                                ##STR67##  CO.sub.2 H                                                                          H   Single bond                               303                                                                               -n-propyl                                                                                ##STR68##  CO.sub.2 H                                                                          H   Single bond                               304                                                                               -n-propyl                                                                                ##STR69##  CO.sub.2 H                                                                          H   Single bond                               305                                                                               -n-propyl                                                                                ##STR70##  CO.sub.2 H                                                                          H   Single bond                               306                                                                               -n-propyl                                                                                ##STR71##  CO.sub.2 H                                                                          H   Single bond                               307                                                                               -n-propyl                                                                                ##STR72##  CO.sub.2 H                                                                          H   Single bond                               308                                                                               -n-propyl                                                                                ##STR73##  CO.sub.2 H                                                                          H   Single bond                               309                                                                               -n-propyl CHCHCH.sub.2 OH                                                                           CO.sub.2 H                                                                          H   Single bond                               310                                                                               -n-propyl CHCHCH.sub.2 OCH.sub.3                                                                    CO.sub.2 H                                                                          H   Single bond                               311                                                                               -n-propyl CHCHCH.sub.2 OC.sub.2 H.sub.5                                                             CO.sub.2 H                                                                          H   Single bond                               312                                                                               -n-propyl CHCHCH.sub.2 O- -n-C.sub.3 H.sub.7                                                        CO.sub.2 H                                                                          H   Single bond                               313                                                                               -n-propyl                                                                                ##STR74##  CO.sub.2 H                                                                          H   Single bond                               314                                                                               -n-propyl                                                                                ##STR75##                                                      315                                                                              CHCHCH.sub.3                                                                             CH.sub.2 COPh                                                                             CO.sub.2 H                                                                          H   Single bond                               316                                                                              CHCHCH.sub.3                                                                             CH.sub.2 COCH.sub.2 Ph                                                                    CO.sub.2 H                                                                          H   Single bond                               317                                                                              CHCHCH.sub.3                                                                             CH.sub.2 CO(CH.sub.2).sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               318                                                                              CHCHCH.sub.3                                                                             CH.sub.2 CO(CH.sub.2).sub.3 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               319                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.4 COCH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               320                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.5 COCH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               321                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.6 COCH.sub.2 Ph                                                            CO.sub.2 H                                                                          H   Single bond                               322                                                                              CHCHCH.sub.2 CH.sub.3                                                                     ##STR76##  CN.sub.4 H                                                                          H   Single bond                               323                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 SCH.sub.3                                                                        CO.sub.2 H                                                                          H   Single bond                               324                                                                              CHCHCH.sub.2 CH.sub.3                                                                     ##STR77##  CO.sub.2 H                                                                          H   Single bond                               325                                                                              CHCHCH.sub.2 CH.sub.3                                                                     ##STR78##                                                      326                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 CH.sub.3                                                              CO.sub.2 H                                                                          H   Single bond                               327                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 Et                                                                    CO.sub.2 H                                                                          H   Single bond                               328                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 - -n-C.sub.3 H.sub.7                                                  CO.sub.2 H                                                                          H   Single bond                               329                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO- -n-C.sub.4 H.sub.9                                                         CO.sub.2 H                                                                          H   Single bond                               330                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 - -n-C.sub.5 H.sub.11                                                 CO.sub.2 H                                                                          H   Single bond                               331                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 - -n-C.sub.6 H.sub.11                                                 CO.sub.2 H                                                                          H   Single bond                               332                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                                           CO.sub.2 H                                                                          H   Single bond                               333                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 CF.sub.3                                                              CO.sub.2 H                                                                          H   Single bond                               334                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub. 2 CH.sub.3                                                             CO.sub.2 H                                                                          H   Single bond                               335                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 CF.sub.3                                                              CO.sub.2 H                                                                          H   Single bond                               336                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 C.sub.2 F.sub.5                                                       CO.sub.2 H                                                                          H   Single bond                               337                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 - -n-C.sub.3 F.sub.7                                                  CO.sub.2 H                                                                          H   Single bond                               338                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 - -n-C.sub.4 F.sub.9                                                  CO.sub.2 H                                                                          H   Single bond                               339                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 - -n-C.sub.5 F.sub.11                                                 CO.sub.2 H                                                                          H   Single bond                               340                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 - -n-C.sub.6 F.sub.13                                                 CO.sub.2 H                                                                          H   Single bond                               341                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                                           CO.sub.2 H                                                                          H   Single bond                               342                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 F  CO.sub.2 H                                                                          H   Single bond                               343                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 CN.sub.4 H                                                                       CO.sub.2 H                                                                          H   Single bond                               344                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 Ph                                                                    CO.sub.2 H                                                                          H   Single bond                               345                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 (CH.sub.2).sub.2 Ph                                                   CO.sub.2 H                                                                          H   Single bond                               346                                                                              CHCHCH.sub.2 CH.sub.3                                                                    CH.sub.2 NHCO.sub.2 (CH.sub.2).sub.3 Ph                                                   CO.sub.2 H                                                                          H   Single bond                               347                                                                              CHCH(CH.sub.2).sub.2 CH.sub.3                                                            H           CO.sub.2 H                                                                          H   CO                                        348                                                                              CHCH(CH.sub.2).sub.3 CH.sub.3                                                            H           CO.sub.2 H                                                                          H   CO                                        349                                                                              CCCH.sub.3 CH.sub.2 OH CO.sub.2 H                                                                          H   CO                                        350                                                                              CCCH.sub.2 CH.sub.3                                                                      CH.sub.2 OH CO.sub.2 H                                                                          H   CO                                        351                                                                              CC(CH.sub.2).sub.2 CH.sub.3                                                              CH.sub.2 OH CO.sub.2 H                                                                          H   CO                                        352                                                                              CC(CH.sub.2).sub.3 CH.sub.3                                                              CH.sub.2 OH CO.sub.2 H                                                                          H   CO                                        353                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          NO.sub.2                                                                          NHCO                                      354                                                                               -n-propyl CO.sub.2 H  CO.sub. 2 H                                                                         OCH.sub.3                                                                         NHCO                                      355                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          CH.sub.3                                                                          NHCO                                      356                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          F   NHCO                                      357                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          Cl  NHCO                                      358                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          Br  NHCO                                      359                                                                               -n-propyl CO.sub.2 H  NHSO.sub.2 CF.sub.3                                                                 I   NHCO                                      360                                                                               -n-propyl CO.sub.2 H  CO.sub.2 H                                                                          H   OCH.sub.2                                 361                                                                              CHCHCH.sub.3                                                                             CH.sub.2 OCH.sub.3                                                                        CO.sub.2 H                                                                          H   O                                         362                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.2 OCH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                               363                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.3 OCH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                               364                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.4 OCH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                               365                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.5 OCH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                               366                                                                              CHCHCH.sub.3                                                                             (CH.sub.2).sub.6 OCH.sub.3                                                                CO.sub.2 H                                                                          H   Single bond                               367                                                                              CHCHCH.sub.3                                                                             CH.sub.2 OCH.sub.2 CH.sub.3                                                               CO.sub.2 H                                                                          H   Single bond                               368                                                                              CHCHCH.sub.3                                                                             CH.sub.2 O(CH.sub.2).sub.2 CH.sub.3                                                       CO.sub.2 H                                                                          H   Single bond                               369                                                                              CHCHCH.sub.3                                                                             CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                       CO.sub.2 H                                                                          H   Single bond                               370                                                                              n-butyl    CO.sub.2 Et CN.sub.4 H                                                                          H   Single bond                                                                         157-158                             371                                                                              n-butyl    CO.sub.2 H  CN.sub.4 H                                                                          H   Single bond                                                                         190-191                                                                       (dec.)                              372                                                                              n-propyl   CHO         CN.sub.4 H                                                                          H   Single bond                                                                          68-71                              __________________________________________________________________________

The compounds of Examples 370-372 were prepared as follows:

EXAMPLE 370 Part A: Ethyl5-(1-hydroxybutyl)-1-[2'-(1-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure for Example 277,Part B.

From ethyl5-formyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(5.0 g, 7.77 mmol) and n-propylmagnesium chloride (5.8 ml of a 2.0Msolution in ether; 11.6 mmol) was obtained 5.5 g of the title compoundas a yellow viscous oil on workup, used in the following step withoutfurther purification.

NMR (200 MHz; CDCl₃, TMS) δ: 7.77-6.90 (m, 9H), 6.24 (d, J=4 Hz, 1H),5.85 (q, J=17 Hz and 23 Hz, 2H), 4.51 (m, 1h), 4.20 (q, J=7.5 Hz, 2H),1.85 (m, 4H), 1.27 (t, J=7.5 Hz, 3H), 1.21 (s, 9H), 0.95 (t, J=7.5 Hz,3H).

PART B: (Cis- and trans-) ethyl5-(1-butenyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure for Example 277,Part C.

From ethyl5-(1-hydroxybutyl)-1-[2'-(1-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(8.9 g, 12.9 mmol), methanesulfonyl chloride (5.9 ml, 77.6 mmol), andDBU (11.8 ml, 77.6 mmol) in THF (150 ml) was obtained 4.3 g (49%) of thetitle compound as a white solid following flash chromatography on silicagel (400 g; EtOAc/hexanes, 1/4); m.p. 119°-121° C.

NMR (200 MHz; CDCl₃, TMS) δ: 7.88-6.77 (m, 24H), 6.36-6.06 (m, 3H; 2Hvinyl+1H pyrrole), 5.57 (s, 2H), 4.14 (q, J=7 Hz, 2H), 2.10-1.97 (m,2H), 1.25 (t, J=7 Hz, 3H), 0.94 (t, J=7 Hz), 3H).

Part C: Ethyl5-n-butyl-1-[2'(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure for Example 277,Part D.

From (cis- and trans-)ethyl5-(1-butenyl)-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(4.0 g, 5.97 mmol) and 5% Pd/C (0.60 g) in benzene (200 ml) under H2 (40psi) was obtained 3.66 g (91%) of the title compound as a white solidafter filtration and concentration, used subsequently without furtherpurification.

NMR (200 MHz, CDCl₃, TMS) δ: 7.88-6.68 (m, 24H), 6.01 (d, J=4 Hz, 1H),5.53 (s, 2H), 4.15 (q, J=7 Hz, 2H), 2.36 (t, J=7 Hz, 2H), 1.55-1.47 (m,2H), 1.32-1.18 (m and t, J=7 Hz, 5H), 0.83 (t, J=7 Hz, 3H).

Part D: Ethyl5-n-butyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate

This compound was prepared according to the procedure of Example 3, PartC.

In this case, since the starting material was not easily slurried inwater (due to its waxy nature), it was first dissolved in EtOAc. Fromethyl5-n-butyl-1-[2'-1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(3.0 g, 4.45 mmol) in EtOAc/TFA/H₂ O (20 ml/10 ml/10 ml) was obtained1.23 g (64%) of the title compound as a white solid following flashchromatography on silica gel (30 g; EtOAc) and recrystallization(EtOAc/hexanes); m.p. 157°-158° C.

NMR (200 MHz, CDCl₃, TMS) δ: 8.14-6.89 (m, 9H), 6.05 (d, J=4 Hz, 1H),5.59 (s, 2H), 4.15 (q, J=7 Hz, 2H), 2.53 (t, J=7 Hz, 2H), 1.64-1.53 (m,2H), 1.42-1.22 (m and t, J=7 Hz, 5H), 0.90 (t, J=7 Hz, 3H).

EXAMPLE 371 Part A:5-n-Butyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylicacid

This compound was prepared according to the procedure for Example 1,Part C.

From ethyl5-n-butyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxylate(0.97 g, 2.26 mmol) was obtained 0.68 g (75%) of the title compound asan off-white solid following recrystallization (EtOAc/EtOH/hexanes);m.p. 190°-191° C. (dec.).

NMR (200 MHz; CDCl₃, TMS) δ: 7.86-6.82 (m, 9H), 6.05 (d, J=4 Hz, 1H),5.56 (s, 2H), 2.51 (t, J=7 Hz, 2H), 1.62-1.54 (m, 2H), 1.41-1.26 (m,2H), 0.89 (t, J=7 Hz, 3H).

EXAMPLE 372 Part A:5-n-propyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxaldehyde

This compound was prepared according to the procedure for Example 280,Part B.

From 5-n-propylpyrrole-2-carboxaldehyde (2.0 g, 15.1 mmol) and4'-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl (10.9 g, 19.7mmol) was obtained 5.2 g (75%) of the title compound as a yellow solidfollowing flash chromatography (silica gel, 550 g; EtOAc/hexanes, 1/9).

NMR (200 MHz; CDCl₃, TMS) δ: 9.45 (s, 1H), 7.9-6.7 (m, 24H), 6.10 (d,J=2 Hz, 1H), 5.50 (s, 2H), 2.35 (t, J=7 Hz, 2 H), 1.7-1.5 (m, 2 H), 0.8(t, J=7 Hz, 3 H).

Part B:5-n-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxaldehyde

To a solution of5-n-propyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxaldehyde(4.05 g, 6.6 mmol) in THF (25 ml) was added 4N HCl (11 ml) withstirring. The mixture was stirred at room temperature for 5 hours. TheTHF was removed by rotary evaporation and the residue was adjusted to pH5-6 with 4N NaOH (˜10 ml). The product was extracted into EtOAc (2×50ml), the organic layer was dried (MgSO₄), filtered and concentrated.Flash chromatography of the reddish solid residue (1.97 g) on silica gel(30 g; EtOAc/hexanes, 1/1) gave 1.4 g of the title compound as a palepink solid; m.p. 68°-71° C.

NMR (200 MHz; CDCl₃, TMS) δ9.34 (s, 1 H), 7.87-6.86 (m, 9 H), 6.19 (d,J=4 Hz, 1 H), 5.57 (s, 2 H), 2.53 (t, J=7.5 Hz, 2 H), 1.70-1.59 (m, 2H), 0.93 (t, J=7.3 Hz, 3 H).

UTILITY

The hormone angiotensin II (AII) produces numerous biological responses(e.g. vasoconstriction) through stimulation of its receptors on cellmembranes. For the purpose of identifying compounds such as AIIantagonists which are capable of interacting with the AII receptor, aligand-receptor binding assay was utilized for the initial screen. Theassay was carried out according to the method described by [Glossmann etal., J. Biol. Chem., 249, 825 (1974)], but with some modifications. Thereaction mixture contained rat adrenal cortical microsomes (source ofAII receptor) in Tris buffer and 2 nM of ³ H-AII with or withoutpotential AII antagonist. This mixture was incubated for 1 hour at roomtemperature and the reaction was subsequently terminated by rapidfiltration and rinsing through glass micro-fibre filter. Receptor-bound³ H-AII trapped in filter was quantitated by scintillation counting. Theinhibitory concentration (IC₅₀) of potential AII antagonist which gives50% displacement of the total specifically bound ³ H-AII is presented asa measure of the affinity of such compound for the AII receptor (seeTable 4).

The potential antihypertensive effects of the compounds of thisinvention may be demonstrated by administering the compounds to ratsmade hypertensive by ligation of the left renal artery [Cagniano et al.,J. Pharmacol. Exp. Ther., 208, 310 (1979)]. This procedure increasesblood pressure by increasing renin production with consequent elevationof AII levels. Compounds are administered orally and/or intravenouslyvia a cannula in the jugular vein. Arterial blood pressure iscontinuously measured directly through a carotid artery cannula andrecorded using a pressure transducer and a polygraph. Blood pressurelevels after treatment are compared to pretreatment levels to determinethe antihypertensive effects of the compounds (See Table 5).

DOSAGE FORMS

The compounds of this invention can be administered for the treatment ofhypertension according to the invention by any means that effectscontact of the active ingredient compound with the site of action in thebody of a warm-blooded animal. For example, administration can beparenteral, i.e., subcutaneous, intravenous, intramuscular, orintraperitoneal. Alternatively, or concurrently, in some casesadministration can be by the oral route.

The compounds can be administered by any conventional means availablefor use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. They canbe administered alone, but are generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. Diuretics such asfurosemide and hydrochlorothiazide may enhance the antihypertensiveeffect of the compounds of this invention when the drugs areadministered in physical combination or when a diuretic is administeredbefore the compound of this invention. The compounds of this inventioncan be used in conjunction with non-steroidal anti-inflammatory drugs(NSAID's) such as ibuprofen, indomethacin, piroxicam, naproxen,ketoprofen, tolmetin, meclofenamate, sulindac and azapropazone toprevent the renal failure that sometimes occurs upon administration ofNSAID's.

For the purpose of this disclosure, a warm-blooded animal is a member ofthe animal kingdom possessed of a homeostatic mechanism and includesmammals and birds.

The dosage administered will be dependent on the age, health and weightof the recipient, the extent of disease, kind of concurrent treatment,if any, frequency of treatment and the nature of the effect desired.Usually, a daily dosage of active ingredient compound will be from about0.5 to 500 milligrams per kilogram of body weight. Ordinarily, from 1 to100, and preferably 2 to 80, milligrams per kilogram per day in one ormore applications is effective to obtain desired results.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methylor propylparaben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

CAPSULES

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

SOFT GELATIN CAPSULES

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

TABLETS

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

INJECTABLE

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol. The solution is made to volume with water forinjection and sterilized.

SUSPENSION

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 100 milligrams of finely divided active ingredient,100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

                  TABLE 5                                                         ______________________________________                                               Angiotensin II                                                                            Antihypertensive                                                  Receptor    Effects in Renal                                                  Binding     Hypertensive Rats                                          Example  IC.sub.50     Intravgenous                                                                             Oral                                        No.      μ molar    Activity.sup.1                                                                           Activity.sup.2                              ______________________________________                                        1        3.0           NA         NA                                          2        1.0           +          +                                           3        6.0           +          +                                           4        0.3           +          +                                           67       0.82          +          NA                                          68       1.8           +          NA                                          69       0.73          +          NA                                          70       5.0           +          NA                                          71       0.82          +          NA                                          72       0.14          +          +                                           170      7.3           +          NA                                          171      0.29          +          +                                           172      0.72          +          +                                           173      6.7           +          +                                           174      >1.0          +          NA                                          175      9.5           +          NT                                          176      2.3           NA.sup.3   NA.sup.3                                    177      >3.0          NA.sup.3   NA.sup.3                                    178      4.1           +          +                                           179      >3.0          NA.sup.3   NA.sup.3                                    277      1.6           +          +                                           278      >3.0          NA.sup.3   NA.sup.3                                    279      >12.0         +          +                                           ______________________________________                                         .sup.1 Significant decrease in blood pressure at 10 mg/kg or less.            .sup.2 Significant decrease in blood pressure at 100 mg/kg or less.           NA.sup.3 -- Not active at 30 mg/kg i.v. or 30 mg/kg p.o.                      NA -- Not active at 100 mg/kg dosage administered.                            NT -- Not tested.                                                        

We claim:
 1. A method of treating hypertension in a warm-blooded animalin need of such treatment comprising administering to the animal in anamount effective to lower the animal's blood pressure a compound of theformula: ##STR79## or a pharmaceutically suitable salt thereof, whereinA is a carbon-carbon single bond, CO, O, NHCO, or OCH₂ ;R¹ is alkyl of 2to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, or(CH₂)_(n) OR⁴ provided that when R¹ is (CH₂)_(n) OR⁴ then R² is H, alkylof 2 to 6 carbon atoms, or alkenyl or alkynyl of 3 to 6 carbon atoms; R²is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbonatoms; --(CH₂)_(n) OR⁴ ; --(CH_(2m) COR⁶ ; --(CH₂)_(n) OCOR⁴ ;--(CH₂)_(n) S(O) R⁴ ; --(CH═CH(CH₂)_(m) CR⁴ HOR¹² ; --CH═CH(CH₂)_(m)COR⁶ ; --(CH₂)_(n) NHCOOR¹¹ ; --(CH₂)_(n) NHSO₂ R¹¹ ; --(CH₂)_(n) F; or##STR80## R³ is CO₂ H, --NHSO₂ CF₃ ; or ##STR81## R⁴ is H or alkyl of1-4 carbon atoms; R⁵ is H, halogen, NO₂, methoxy, or alkyl of 1 to 4carbon atoms; R⁶ is H, alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to6 carbon atoms, (CH₂)_(m) C₆ H₅, OR⁷ or NR⁸ R⁹ ; R⁷ is H, alkyl of 1 to5 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; phenyl or benzyl; R⁸and R⁹ are independently H, alkyl of 1 to 4 carbon atoms, phenyl, orbenzyl; or NR⁸ R⁹ taken together form a ring of the formula: ##STR82## Ois NR¹⁰, O or CH₂ ; R¹⁰ is H, alkyl of 1 to 4 carbon atoms or phenyl;R¹¹ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbonatoms or (CH₂)_(p) C₆ H₅ ; R¹² is H, alkyl of 1 to 4 carbon atoms, oracyl of 1 to 4 carbon atoms; m is 0 to 6; n is 1 to 6; p is 0 to 3; r is0 to 1; t is 0 to
 2. 2. The method of treatment of claim 1 wherein forthe formula:A is a carbon-carbon single bond or NHCO; R¹ is alkyl,alkenyl or alkynyl, each of 3 to 5 carbon atoms; R² is H, alkyl, alkenylor alkynyl, each of 3 to 5 carbon atoms;--(CH₂)_(n) OR⁴ ; --(CH₂)_(m)COR⁶ ; --(CH₂)_(n) OCOR⁴ ; --CH═CH(CH₂)_(m) CR⁴ HOR¹² ; --CH═CH(CH₂)_(m)COR⁶ ; --(CH₂)_(n) NHCOOR¹¹ ; --(CH₂)_(n) NHSO₂ R¹¹ ; --(CH₂)_(n) F; or##STR83## R⁴ is H or CH₃ ; R⁵ is H; R⁶ is H, alkyl of 1 to 6 carbonatoms; OR⁷ or NR⁸ R⁹ ; R⁷ is alkyl of 1 to 5 carbon atoms; R⁸ and R⁹ areindependently H or alkyl of 1 to 4 carbon atoms; or NR⁸ R⁹ takentogether form a ring of the formula: ##STR84## R¹¹ is alkyl of 1 to 4carbon atoms, CF₃ or phenyl; m is 0 to 3; n is 1 to 3;or apharmaceutically suitable salt thereof.
 3. The method of treatment ofclaim 2 wherein,A is a carbon-carbon single bond; R¹ is alkyl or alkenylof 3 to 5 carbon atoms; R² is alkyl or alkenyl of 3 to 5 carbon atoms;--CH₂ OR⁴ ; --COR⁶ ; --CH₂ COR⁶ ; --CH₂ OCOR⁴ ; or --CH₂ NHCOOR¹¹ ; R⁶is H, alkyl of 1 to 4 carbon atoms or OH; or a pharmaceutically suitablesalt thereof.
 4. The method of treatment of claim 3 wherein the compoundis 5-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-1,2,3-triazole, or apharmaceutically suitable salt thereof.